Abstract
This chapter provides the reader with a collection of endogenous DAMPs in terms of constitutively expressed native molecules. The first class of this category refers to DAMPs, which are passively released from necrotic cells, and includes the most prominent subclasses of high mobility group box I and heat shock proteins. Further subclasses of DAMPs that are passively released from necrotic cells include S100 proteins, nucleic acids, histones, pro-forms of interleukin-1-family members, mitochondria-derived N-formylated peptides, F-actin, and heme. A particular subclass of these passively released DAMPs are molecules, which indirectly activate the inflammasome, including adenosine-5′-triphosphate, monosodium urate crystals, cholesterol crystals, some lipolytic species, and beta-amyloid. All these passively released DAMPs are characterized by their capability to promote necroinflammatory responses. The second class of this Category I refers to molecules, which are exposed on the surface of stressed cells. They include the subclass of phagocytosis-facilitating molecules such as calreticulin, as well as the subclass of MHC-I-related molecules such as MHC-I-related molecule A and B. These DAMPs are capable of inducing the activation of innate lymphoid cells and unconventional T cells. One of these DAMPs, the major histocompatibility complex I-related molecule A, is shown to act as a bona fide transplantation antigen. In sum, the endogenous constitutively expressed native molecules represent an impressive category of DAMPs with extraordinary properties, which play a critical role in the pathogenesis of many human diseases.
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1 Introduction
Endogenous DAMPs which are constitutively expressed in their native state are denoted as Cat. I DAMPs. Depending on their mode of emission, they comprise molecules passively released from necrotic cells, actively exposed at the surface of stressed cells, and actively secreted by stressed or dying cells. This category of danger signals includes molecules that are regarded as the “prototypical” or “historical” DAMPs which marked the start of the era of DAMPs; the HMGB1 and HSPs can be found among these molecules but also proteins of entirely different nature, structure, and function such as MHC Class I chain-related proteins.
Of note, some of the DAMPs described in this but also other subsequent chapters refer to so-called Hyppos in terms of proteins or lipids with hydrophobic surfaces. These hydrophobic molecules have been characterized by Seong and Matzinger already very early (in 2004!) as integral parts of endogenous DAMPs [1]. For example, as outlines in this anecdotal article, uric acid, HSPs, and hyaluronan (HA) polymers (held together by evenly spaced hyppos) have such hydrophobic binding sites. In the following, they will be described under the various subchapters concerned.
Together, the global role of the Cat. I DAMP in the initiation of various efferent innate immune pathways and adaptive immune responses justifies their description in the first chapter.
2 DAMPs Passively Released from Necrotic Cells (Class IA DAMPs)
2.1 Introductory Remarks
In case of ACD or RN as defined by a complete rupture of the plasma membrane, the whole content of the cell is passively released. The various intracellular native compounds including organelles and cell debris operate in the extracellular milieu as constitutively expressed native DAMPs, denoted here as Class IA DAMPs (for ACD and RN, compare Part V, Chap. 17 and Sect. 19.3). Most of these DAMPs such as HMGB1 [2,3,4], HSPs [5,6,7], S100A8/A9 proteins [8, 9], and NAs [10, 11] can be directly sensed via binding to a variety of PRMs. These PRMs in terms of “classical” PRRs include TLRs, CLRs, NLRs, ALRs along with other DNA receptors such as cGAS, and RAGE (for informing articles, see Refs. [10, 12,13,14,15,16,17,18,19,20,21]). Many of these Class IA DAMPs signal danger to the surrounding PRMs-bearing cells such as leukocytes and phagocytes to trigger sterile inflammation and to PRM-bearing DCs to elicit adaptive immunity. In addition, some of these Class IA DAMPs were shown to activate sessile PRM-bearing cells of the innate immune system such as fibroblasts, myofibroblasts, and epithelial and vascular cells, thereby promoting repair and regeneration, for example, wound-healing processes following infectious/sterile injury-induced inflammation (for relevant articles, see Refs. [22,23,24,25,26,27]).
In the following, those DAMPs will be described which are predominantly or exclusively recognized by TLRs such as TLR4 and TLR2 (but also by RAGE ) as well as NA receptor molecules such as RIG-I and cGAS. Historically, HSP72 plays a particular role as such a DAMP, because descriptions of endogenous agonists of TLRs up-regulated in vivo during sterile tissue injury started with this molecule [28]. Up to now, however, HMGB1 is the by far most investigated DAMP . Thus, these two molecules will be addressed in more detail.
2.2 The Prototype of DAMPs: High Mobility Group Box 1 (Subclass IA-1 DAMP)
2.2.1 General Remarks
The high mobility group (HMG) nuclear proteins were discovered in 1973 in an effort to better define the specific regulators of gene expression. Regarding their quick migration during electrophoresis, they were named after this property [29]. As a member of a subfamily of the HMG proteins, HMGB1 is both a nucleus-resident factor released following cell membrane rupture and—under certain conditions—a secreted (modified) protein (see also below, Sect. 14.3.3). As an intracellular nonhistone chromatin-associated protein, it operates as a DNA chaperone under homeostatic conditions by binding the DNA double helix transiently and bending it reversibly. As a DNA chaperone, the protein enhances the formation of nucleosomes; contributes to the assembly of site-specific DNA binding proteins to their cognate binding sites within chromatin, including transcription factors that underwind DNA upon binding; and is involved in transcription, replication, and DNA repair. Indeed, HMGB1 is an extremely mobile protein. The entire pool of HMGB1 roams the nucleus, resting on a specific DNA site for only fractions of a second. The transient binding to chromatin enables HMGB1 to perform its activities in transcription and other nuclear transactions [30]. The native HMGB1 is constitutively expressed in almost all cell types, and to operate as a DAMP, it is passively released following ACD or RN. Of note, in terms of an inducible DAMP, HMGB1 is actively secreted in a processed/modified state during severe stress (for competent articles and reviews, see Refs. [31,32,33,34]).
Clearly, the history of the development of the molecule and current knowledge of its function are fascinating. During recent years, the number of investigations on HMGB1 is steadily growing. Justifiably, today, one can state that HMGB1 is apparently the best characterized DAMP. By utilizing comprehensive review articles as a guide (see Refs. [30, 31, 35,36,37]), a brief summary of the properties of this most relevant DAMP is depicted in the following.
2.2.2 The High Mobility Group Box Family of Proteins
The HMG proteins comprise three families: HMG-A, HMG-N, and HMG-box (HMGB) proteins. The HMGB proteins are by far the largest group, playing critical roles in recognition and maintenance of DNA in DNA-dependent cellular processes (reviewed in [38]). The HMGB family in mammals comprises the three evolutionarily highly conserved proteins HMGB1 (previously HMG1), HMGB2 (previously HMG2), and HMGB3 (previously HMG4 or HMG2b).
High mobility group box protein 1, an abundant 215 amino acid residue-containing protein present at variable levels in almost all mammalian tissues and cells, is highly conserved among various species. The molecule has a tripartite structure and consists of two homologous L-shaped DNA-binding domains (termed N-terminal HMG A box and central HMG B box) and a negatively charged (acidic) C-terminal tail. The tail interacts with the HMG boxes and may modulate their intermolecular interactions (for relevant articles, see [34, 39,40,41,42]) (Fig. 12.1). These separate structural motifs seem to function in different ways when isolated from HMGB1. Thus, several studies have identified the B-box domain as important for many of the pro-inflammatory properties of HMGB1 including cytokine release. In comparison, the A-box does not have the pro-inflammatory capabilities of the B-box and instead competes with HMGB1 for binding sites leading to mitigation of the inflammatory cascade [43].
2.2.3 Release of HMGB1 from Necrotic Cells Upon Sterile and Infectious Tissue Injury
Necrotic cells passively release HMGB1 and trigger sterile inflammation [44, 45]. As shown in early experiments performed by Scaffidi et al. [32], HMGB1 is released passively during cellular necrosis by almost all cells, which have a nucleus, and signals neighboring cells of ongoing damage. These early findings were convincingly confirmed by in vitro studies on Jurkat T cell leukemia cells treated to induce necrosis in terms of ACD by freeze-thawing, heat, hydrogen peroxide, or ethanol [46]. Among treatments tested, freeze-thawing produce the highest levels of extracellular HMGB1. Similar lines of studies are in support of these findings by showing an important role for oxidative stress mediated by hydrogen peroxide (H2O2) in inducing passive HMGB1 release from macrophages and monocytes in a time- and dose-dependent manner [47]. Indeed, there is now general agreement that the death modalities of ACD but also RN (i.e., necroptosis, pyroptosis, and NETosis, described in Part V, Chap. 17 and Sect. 19.3) represent a huge source of the passive emission of this DAMP (reviewed in Refs. [48,49,50,51]).
Typical sterile tissue injuries causing passive release of HMGB1 from dying cells include ROS-mediated oxidative damage such as IRI [52, 53], traumatic lesions in patients [54,55,56,57], or chemically induced toxic liver injuries [58, 59] (reviewed by Lu et al. in Ref. [34]). As also competently examined by Lu et al. [34], HMGB1 can be passively released from cells infected by various viruses (such as West Nile, salmon anemia, dengue, and influenza viruses), indicating HMGB1 to operate as a critical mediator and amplifier of infectious tissue injury to elicit of virus-induced inflammatory diseases [60]. More recent data from studies in children suffering from enterovirus 71-induced hand, foot, and mouth disease suggest that HMGB1 is involved in the inflammatory pathogenesis of this disease and that the serum level of HMGB1 could be applied as a clinical indicator for the severity of the viral infection [61]. Another recent report presented evidence for a role of HMGB1 as a potential biomarker for severe viral hemorrhagic fevers [62].
2.2.4 The Binding Step: Recognition of HMGB1 Through Pattern Recognition Molecules
Innate immune functions of HMGB1 are mediated by its binding to receptors operating in the innate immune system, the PRRs/PRMs (see Part II) . Several important receptors have been implicated in HMGB1 signalling either via direct binding of HMGB1 or its indirect binding in complex with other molecules.
2.2.4.1 Receptor for Advanced Glycation End Products
The first receptor described for HMGB1 is the RAGE, a multifunctional transmembrane protein of the immunoglobulin (Ig) superfamily [63] (see also Part II, Sect. 5.2.8). Signalling through RAGE results in activation of the transcription factors NF-kB and MAPKs [64] (compare Part VI, Sect. 22.3.9). In particular, activation of the extracellular signal-regulated protein kinase (ERK) MAPK pathway is crucial in mediating cell migration, tumor proliferation and invasion, and expression of MMPs. Indeed, the HMGB1 → RAGE axis is critically involved in the recruitment and migration of cells, directly by inducing expression of adhesion molecules, such as ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1) [65], or indirectly by causing secretion of chemokines, in particular CXCL12, which in turn forms a heterocomplex with HMGB1 [66] (for chemokines and adhesion molecules, see Part VI, Sects. 22.5.11 and 22.5.12).
2.2.4.2 Toll-Like Receptors
Besides RAGE, the Toll-like family of receptors has been demonstrated to be important in recognition of the DAMP HMGB1 associated with subsequent HMGB1-triggered signalling. Already in 2004, TLR4 and TLR2 were reported to be such candidates [67]: Murine macrophage cell lines transfected with dominant-negative constructs of TLR2 and TLR4 were found to show a decreased activation on stimulation with HMGB1. In particular, a decrease in NF-κB-dependent reporter gene expression after transfection with dominant-negative constructs to TLR2, TLR4, or both, demonstrated that TLR2 and TLR4 are both involved in HMGB1-induced activation of NF-κB [67]. Most crucial evidence in support of the notion that injury-induced HMGB1 is recognized by TLR4 came from the early seminal experiment performed by the Pittsburgh group [68]: TLR4-defective mice (C3H/Hej mice) exhibited less damage in the hepatic postischemic reperfusion model than did wild-type mice (C3H/HeOuj mice). Anti-HMGB1 antibody failed to provide protection in C3H/Hej mice but successfully reduced damage in C3H/Ouj mice. These Pittsburgh results demonstrated that HMGB1 is an early mediator of injury and inflammation in liver IRI and implicates TLR4 as one of the receptors that are involved in the process [68].
During the past decade, the contribution of the HMGB1 → TLR4 axis to inflammation and immune regulation has been demonstrated in a wide range of experimental models, such as liver and lung damage, cancer, and epilepsy (reviewed by Venereau et al. [31]). In addition, other lines of studies revealed that HMGB1, when bound to nucleosomes, activates macrophages and DCs through TLR2 [69] and, when complexed with CpG oligodeoxynucleotides (ODNs), binds to TLR9 to enhance cytokine production in pDCs [30, 70].
2.2.4.3 HMGB1 Promiscuously Binds Multiple MAMPs
Intriguingly, HMGB1 was observed to form complexes with almost all kinds of NAs as well as LPS, promoting sensing by their cognate receptors and increasing the robustness of inflammatory and immune responses to those agents. As a matter of fact, high-purity HMGB1 was even discussed to possess a limited pro-inflammatory activity on its own (for competent articles, see Refs. [70,71,72,73]). On the other hand, one may speculate that those MAMPs concerned may only acquire immunogenicity by complexing with HMGB1.
2.2.5 Redox Status-Dependent Functions of High Mobility Group Box 1
Once in the extracellular milieu, HMGB1 signals danger to the surrounding cells, triggers inflammation, and activates innate and adaptive immunity by interacting with multiple receptors mentioned above. Intriguingly, however, these various functions of HMGB1 vary depending on the redox state of this prototypical DAMP. Thus, the redox status of HMGB1 reportedly distinguishes its cytokine-inducing and chemokine activity. In fact, a large body of evidence has been published demonstrating that the redox state of cysteines modulates the binding of HMGB1 to its receptors and consequently its activities (reviewed by Venereau et al. [31]). The puzzle is based on three cysteines in positions 23, 45, and 106 possessed by HMGB1: C23 and C45 can form a disulfide bond, and C106 is unpaired. These cysteines are modified by redox reactions, causing three isoforms called fully reduced HMGB1 for the all-thiol form, disulfide HMGB1 for the partially oxidized one, and sulfonyl HMGB1 for the terminally oxidized form [74] (Fig. 12.2). Fully reduced HMGB1 has sole chemokine activity by creating a complex with the chemokine CXCL12, which binds with increased affinity to its CXCR4 receptor to promote recruitment of inflammatory cells to sites of damaged tissues [66]. Conversely, the myeloid differentiation factor 2 (MD-2), an extracellular adaptor of TLR4, binds specifically to disulfide HMGB1 but not to the other redox forms, thereby triggering the upregulation of chemokines and cytokines [75] (for MD-2, see Part VI, Sect. 22.3.3.1). Of note, interaction with MD-2 also requires the third cysteine, in the fully reduced form. Thus, the disulfide bond between C23 and C45 qualifies HMGB1 as a pro-inflammatory cytokine, whereas further cysteine oxidation to sulfonates abolishes both the chemoattractant and pro-inflammatory activities of HMGB1 [45]. Also, reduced HMGB1 protein promotes autophagy, whereas oxidized HMGB1 fosters apoptosis (for autophagy and apoptosis, compare Part V, Sects. 18.2 and 19.2). Further and for clinicians essential to know, a correlation between the presence of the disulfide HMGB1 and the onset of pathologies could be clinically shown, for example, concerning brain injury, liver damage, myositis, and juvenile idiopathic arthritis (reviewed in [31]). Remarkably, disulfide HMGB1, and not the reduced form, contributes to nociceptive signal transmission via activation of TLR4 [76] (for nociceptors sensing exogenous DAMPs, compare below, Chap. 15).
Apart from redox status-mediated HMGB1 changes, many PTMs have been identified in altering HMGB proteins, including acetylation, phosphorylation, methylation, and oxidation [77] (for PTMs, see also Part VI, Sect. 24.3). These PTMs lead to different functional consequences, whereby acetylation obviously enables the molecule to be secreted. In fact, acetylation of Lys 75 (K73 in humans) in Sox 2 was shown to promote transport of the molecule from the nucleus to the cytoplasm, indicating that acetylation of HMG boxes might serve as a transport signal for this entire class of proteins [38, 78] (for secreted HMGB1 acting as an inducible DAMP, see below Sect. 14.3.3).
Together, at the time being, it is now essential and unavoidable to identify the redox state of HMGB1 as well as its potential modification in each specific condition and under given circumstances in vivo (for redox HMGB1, further reading is recommended in [79, 80]).
2.2.6 Concluding Remarks
As already mentioned above, HMGB1 is by far best investigated DAMP induced by tissue injury.
The proven generation of this molecule during all kinds of sterile tissue injury positions this molecule in the center of initiating steps leading to the development of acute and chronic inflammatory processes as well as adaptive immune responses against bacterial and viral antigens, as well as autoantigens to promote autoimmune diseases and alloantigens to induce transplant rejection. The intense capability to operate as a DAMP may lie in the fact that it is recognized by three different receptors, TLR4 , TLR2 , and RAGE and, importantly, when complexed with NAs or other MAMPs and DAMPs, to be sensed by their cognate receptors.
2.3 Heat Shock Proteins (Subclass IA-1 DAMPs)
2.3.1 General Remark
All organisms respond to heat by synthesizing a group of stress proteins called heat shock proteins (HSPs). These highly conserved biomolecules exist ubiquitously throughout the evolutionary scale, from archaebacteria to eubacteria, from plants to animals, and from animals to humans [81]. They are abundant across species in nearly all subcellular compartments. They are both constitutively and inducibly expressed. After a sudden rise in temperature of a few degrees, all cells immediately, but transiently, activate a small number of specific genes. Some of these encode HSPs. First observed in 1962, chromosomal “puffing” owing to the “unwrapping” of chromatin for gene activation occurred after the exposure of isolated salivary glands of the fruit fly, Drosophila melanogaster, to temperatures slightly above physiological levels [82]. By 1974, “puffing” was noted to be accompanied by high-level expression of a unique set of HSPs [83]. Investigations on Drosophila showed that each of four members of a small HSP family was induced during development in response to heat stress via cell-specific enhancers in the gene promoter regions [84]. Investigations into members of different species soon revealed that cells produce neosynthesized proteins when exposed not only to an abrupt increase in temperature but also to other diverse toxic stress situations such as alterations in the intracellular redox environment or exposure to oxidants, heavy metals, alcohol, xenobiotics, or viral infection. For this reason, they are referred to as “stress proteins” and are divided into different families according to their molecular size, for example, HSP100, HSP90, HSP70, HSP60, HSP40, and HSP20. One of the most intensively studied protein families is the 70-kDa HSP70 [85] (Fig. 12.1). As major stress-inducible proteins, the HSP70 family consists of ubiquitous HSP73 and of HSP72, which is inducible by heat shock, oxidative stress, and infection.
2.3.2 Passive Release of Heat Shock Proteins
Initial studies from Gallucci et al. [86] demonstrated that DCs are stimulated by endogenous signals received from stressed, virally infected, or necrosis-induced cells but not by healthy cells or cells undergoing apoptosis. The Srivastava group subsequently demonstrated that necrotic but not apoptotic cell death leads to the release of HSPs including gp96, HSP90, and the inducible HSP70 family member, HSP72 [87]. These investigators showed that exposure of DCs to necrotic but not apoptotic cells resulted in the nuclear translocation of NF-κB and subsequent maturation of DCs. In more recent times, these early studies were confirmed by several groups. For example, in in vitro experiments on cell lysates, HSP70 released from necrotic monocytes/macrophages was shown to function as an endogenous danger signal to augment the pro-inflammatory responses in monocytes/macrophage [88]. In other lines of studies, HSP70 was found to be passively released from necrotic human prostate carcinoma cells lines treated with hyperthermia [89]. Together, there is sufficient evidence documenting passive release of HSPs form necrotic cells.
2.3.3 The Binding Step: Recognition of Heat Shock Proteins Through Pattern Recognition Molecules
Heat shock proteins such as HSP70 are known to bind to both classical and non-classical PRMs expressed on innate immune cells [90]. For example, as reviewed [5, 91], HSP72 has been shown to bind selectively and with high specificity and affinity to DCs, macrophages, ILCs, and peripheral blood monocytes. Of utmost importance in regard to the initiation of TLR-triggered signalling pathways was the early discovery that HSP72 is recognized by TLR2 and TLR4, together with their cofactor CD14 [92,93,94].
To date, the list of putative HSP receptors has grown and now includes the scavenger receptor CD36 [95,96,97], the costimulatory molecule CD40 [98], the LDL-receptor-related protein CD91[99, 100], and LOX-1 [95, 101], as well as SRA and the class F scavenger receptor expressed by ECs-1 (SREC-1), that is, other members of the scavenger superfamily [96, 102, 103] (for these receptors, also compare Part II, Sects. 5.2.7.3 and 5.3.3) (for scavenger receptors, see Part II, Sect. 5.3.3).
2.3.4 Function of Heat Shock Proteins
That its structure has been widely conserved throughout evolution suggests an essential role in the survival of the organism. In mammalian cells, some HSP family members are present constitutively (“pre-packaged”), act as chaperone molecules, and function as key mediators of proteostasis by controlling protein synthesis, folding, assembly, trafficking, and degradation (“proteostasis” = protein homeostasis). In addition, they contribute to the activity cycle of hormone receptors, including steroid hormones. Through all these functions, they control the quality of newly synthesized proteins and participate in cell homeostasis (for further reading, see Refs. [81, 104,105,106,107]).
The presence and expression of HSPs were originally interpreted as a danger signal for cell stress. Today, we can conclude that the extracellular presence of HSPs in their function as DAMPs, but not their intracellular expression, signals dangerous tissue damage. Indeed, it is now recognized that when present in the cell, they are protective molecules utilized in cellular repair in response to different types of injury, to prevent damage resulting from the accumulation and aggregation of non-native proteins such as oxidized proteins.
Once passively released or actively secreted in the extracellular space, HSPs operate as constitutive DAMPs (for secreted inducible HSPs, see below Sect. 14.2.2.2). Basically, extracellular HSPs appear to function in influencing the inflammatory and immunological balance in tissues. Thus, on the one hand, HSPs, in particular, HSP70 through interaction with TLR4, were demonstrated to promote pro-inflammatory responses [108]; on the other side, they were shown to possess anti-inflammatory properties, thereby qualifying them as so-called DAMPERS or SAMPs [109].
The role of HSPs in the promotion of adaptive immune responses has also two sides. On the one hand, HSPs—when associating with antigenic peptides—reportedly contribute to mounting an adaptive immune response, for example, an anti-tumor immune response by promoting antigen cross-presentation by DCs (reviewed in [90]) (for cross-presentation, see Part VIII, Sect. 31.3.5). On the other hand, HSPs were found to be critical in the induction, proliferation, suppressive function, and cytokine production of Tregs, which maintain peripheral tolerance [110] (for Tregs, see Part VIII, Sect. 33.4.3).
Regarding theses dual functions of extracellular HSPs, Calderwood et al. [90] conclude: “Their effects on the immune system are, thus, bivalent. In the presence of PAMPs or tissues undergoing necrosis, Hsp70, in particular, becomes a strong inflammatory agent. The precise nature of the responses elicited by extracellular HSPs may, therefore, depend upon the particular tissue milieu within which they are released and the identities of the receptors on the surfaces of immune cells that encounter them.”
2.3.5 Concluding Remarks
Strikingly, HSPs operating as DAMPs in the extracellular space are characterized by their bivalent function. In this regard, the conclusion by Calderwood et al. [90] nicely matches with our conclusion made in the discussion of a role of HSP70 in innate alloimmunity [6]: “Altogether, the context-dependent, even contradistinctive activities of HSP70 reflect the biological phenomenon that, throughout evolution, mammals have developed an elaborate network of positive and negative regulatory mechanisms, which provide balance between defensive measures against dangerous bacterial and viral pathogens and protective measures against unwarranted destruction of the host by the activated immune system. Fine-tuning of TLR signaling in amplitude, space, time, and character is a key aspect of inflammatory reactions in health, homeostasis, and pathology. What is becoming more and more apparent is that positive and negative regulators within immune responses do not work as a single entity, but rather, similar to an orchestral score, each component is reliant on its other tools such as HSP70 to produce a harmonious melody instead of a crashing cacophony.”
2.4 Other DAMPs Released from Necrotic Cells (Subclass IA-1 DAMPs)
2.4.1 General Remark
Besides HMGB1 and HSPs, other molecules have been described to be passively released from necrotic cells and to function as extracellular DAMPs. As passively released molecules with chemically different structures, they play expectably various functions. Without mentioned all those contemplable molecules, a few of them are briefly touched in the following.
2.4.2 Passive Release of S100 Proteins
The family of S100 proteins, or calgranulins, is composed of 25 members, and they are names according to their solubility in 100% saturated solution of ammonium sulfate at neutral pH [111] (Fig. 12.1). Of note, several S100 family members have been shown to be released from necrotic cells to acting as critical DAMPs in the promotion of inflammatory responses. The most prominent proteins include S100A8 (also known as calgranulin A or MRP-8), S100A9 (calgranulin B or MRP-14, which can form a dimer with S100A8 extracellularly), S100A12 (calgranulin C or EN-RAGE), and S100B protein (reviewed in [9, 112,113,114,115,116]). The proteins S100A8 and A100A9 are expressed in cells of myeloid origin, including neutrophils and monocytes as well as keratinocytes and epithelial cells under inflammatory conditions. Both proteins can complex, and as a heterocomplex of S100A8/A9, they are often called calprotectin. This complex is highly abundant in human neutrophils and constitutes a large part of the total protein content of these cells. The protein S100A12 binds both zinc and copper and is highly abundant in innate immune cells such as macrophages and neutrophils [117]. The protein S100B is expressed in astrocytes, certain neuronal populations, Schwann cells, melanocytes, chondrocytes, adipocytes, skeletal myofibers and associated satellite cells and DCs and lymphocyte populations, and a few other cell types [118].
2.4.2.1 The Binding Step to TLR4 and RAGE Receptor
After release, extracellular S100A8 and A100A9 were found to interact both with TLR4 and RAGE to exhibit their pro-inflammatory effects, thereby promoting cell migration, proliferation, and differentiation as well as adaptive immune responses [9, 119, 120]. Notably, recent studies were published indicating that CD14 is a co-receptor of TLR4 in the S100A9-induced cytokine response [121]. On the other hand, S100A12 and S100B are reportedly recognized by RAGE, whereby S100A12 has also recently been found to bind to TLR4 to induce monocyte activation [122]. Following recognition, both interactions are known to result in NF-κB-mediated production of pro-inflammatory cytokines [123, 124]. Interestingly, a model was recently proposed, whereby conformational flexibility in the RAGE receptor allows the adoption of a binding conformation for interaction with the stable hydrophobic groove on the surface of S100B [124]. Besides TLR4 and RAGE, other receptors have been identified to sense S100 proteins including GPCRs, scavenger receptors, or heparan sulfate (HS) PGs and N-glycans (reviewed in [125]) (for GPCRs and scavenger receptors, see Part II, Sects. 5.3.3 and 5.3.5).
2.4.2.2 Intracellular Function of S100 Proteins
Intracellularly, S100 proteins are involved in aspects of regulation of proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism, inflammation, and migration/invasion through interactions with a variety of target proteins including enzymes, cytoskeletal subunits, receptors, transcription factors, and NAs [125, 126]. For example, S100A8 and S100 A9 were demonstrated to play a role in Ca2+-dependent interactions between the cytoskeleton and the plasma membrane. In addition, a functional correlation was discovered between the S100A8/A9 heterotetramer and microtubules, promoting polymerization of microtubules in resting phagocytes, which is reversed by the phosphorylated form of S100A8/A9 [9].
2.4.2.3 Concluding Remarks
Together, as concluded elsewhere [125], “S100 proteins are only expressed in vertebrates, and their expression and/or activities appear to be mechanistically linked to the refinement or fine tuning of cell-specific gene expression and responses to external stimuli. Intracellular and extracellular functions of S100 proteins are beginning to be described in detail, making these proteins less enigmatic than in the past. Cardiac function, tissue repair/regeneration, inflammation (including neuroinflammation), infection and cell growth and differentiation, are processes in which certain S100 proteins are active players.”
In fact, their identification as vital DAMPs to promote pro-inflammatory responses is even more critical as they have been shown to be actively secreted by stressed innate immune cells (for details see Sect. 14.2.2.4).
2.4.3 Nucleic Acids
2.4.3.1 General Remarks
Recognition of viral NAs by PRMs is known to be a vital part of our immune defense response to viral infections. Such a response to our own endogenous self NAs is kept in check by several mechanisms under homeostatic conditions because uncontrolled induction of a vigorous innate inflammatory and/or autoimmune response to host-derived NAs might end up with a collateral “suicidal” catastrophe. On the other hand, modern immunological research has revealed that endogenous NAs can nevertheless act as DAMPs in certain circumstances to induce and amplify sterile inflammatory innate immune responses which may transition into autoimmune diseases. Such conditions that reflect a disturbed homeostasis include an oversupply or defects in the NA-degradation machinery (see below) or a misplacement/mislocation of NAs.
2.4.3.2 Passive Release of Nucleic Acids
An oversupply of NAs occurs when, like other cellular components, they are passively released in large amounts from numerous destroyed necrotic cells, which may have undergone ACD or RCD. These NAs include nuclear DNA (nDNA), mitochondrial DNA (mtDNA) containing CpG-DNA repeats (for CpG, see below), and nuclear and cytosolic RNA. For example, the release of endogenous DNA has been observed in the context of NETosis, a subroutine of RCD in which neutrophils actively release their DNA as NETs [127] (for NETs and NETosis, see Part III, Sect. 8.2.3, and Part V, Sect. 19.3.6).
Once released into the extracellular space in these situations, NAs get usually already degraded and—as shown for mtDNA—are oxidatively modified [128, 129]. Following, they are engulfed as cell-extrinsic NAs by neighbored phagocytosing cells such as macrophages, leukocytes, and DCs and subsequently delivered into the endolysosomal system or may even be directly delivered into the cytoplasm. There, they are recognized by and bind to a heterogenous group of PRMs such as TLRs (TLR3, TLR7 → TLR9) and specific DNA and RNA receptors (Fig. 12.3). In the following a few more (oversimplified) details of these sensing procedures are added, guided by recent comprehensive reviews published by Ablasser et al. [131], Roers et al. [130], Miyake et al. [132], and Hartmann [133], where the reader will find much more detailed information.
2.4.3.3 The Binding Step of Engulfed Nucleic Acids
Once arrived after engulfment as cell-extrinsic-emitted DAMPs in the endolysosomal system, NAs are recognized by and bind to lysosomal membrane-bound TLRs, whose NA-binding domains face the lumen of the endolysosomal compartment (also compare Part II, Sect. 5.2.2.4). Thus, DNA is sensed by TLR9, whereby this receptor recognizes a specific sequence pattern, that is, unmethylated CpG dinucleotides (CpG-DNA) called the “CpG motif,” a hexamer, containing a cytosine triphosphate deoxynucleotide (“C”) followed by a guanine triphosphate deoxynucleotide (“G”). The “p” refers to the phosphodiester link between consecutive nucleotides. Long dsRNA is sensed by TLR3, a receptor that was the first bona fide PRR identified as a sensor for dsRNA. TLR3 is not present in the cytosol of healthy cells and thus is regarded as receptor sensing dsRNA coming from outside the cell. Further, TLR7 senses even short RNA, preferentially double-stranded and containing guanine and uridine. The TLR8 functions as receptors for uridine-rich RNA molecules which are likely to be degraded from ssRNA fragments. Notably, TLR7 is expressed in B cells, pDCs, and macrophages, whereas TLR8 is expressed in macrophages and DCs.
Of note, recent attention has been paid to an emerging role of the processing of NAs and TLRs as a mandatory prerequisite to allowing initiation of innate immune responses to NAs (reviewed in [132]). In fact, NA degradation by DNases and RNases has been recognized as a key role in preventing hazardous activation of NA sensors that may become deleterious for the host. For example, DNA degradation by lysosomal (and cytoplasmic) DNases is now known to prevent deleterious homeostatic activation of cytosolic DNA-sensing pathways. As a matter of fact, crude NAs are not effective for stimulating NA receptors. Intriguingly, lysosomal TLRs are also dependent on NA processing in lysosomes. Thus, digestion of dsDNA by DNase II was shown to be required for TLR9 response to ssDNA. Furthermore, TLR7 and TLR8 respond to ribonucleosides and ODNs, instead of ssRNA itself, indicating a requirement for RNA processing. Nucleic acid-sensing TLRs themselves need to be processed by lysosomal proteases. Without processing, TLR8 and TLR9 were found to fail to form dimers. Together, as stressed [132], “the processing of NAs and TLRs has the key role in keeping NA sensors responsive to microbial NAs without inducing hazardous responses to endogenous NAs.”
In case cell-extrinsic NAs are directly delivered into the cytoplasm, they behave as cell-intrinsic NAs and bind to specific cytosolic NA receptors. This scenario is described below in Sects. 13.4.3 and 13.4.4).
2.4.3.4 Extracellular Function of Nucleic Acids
Nucleic acids possess immunostimulatory capacities and are regarded as the keys to defend against viral infections [134]! Hard to believe but already more than 100 years ago, the Polish-German surgeon von Mikulicz-Radecki treated patients with severe surgical peritoneal infections with NAs and other similar substances. The aim was to induce massive hyperleukocytosis, which would increase natural resistance to the bacteria involved. Von Mikulicz-Radecki reported his clinical trial findings at the 33rd Congress of the German Society of Surgeons in 1904 (cited in [135]). Many years later, one of the first reports was published that historically documented the immunostimulatory potential of DNA, in fact, depending on a TLR-independent phenomenon [136]. Still, the mechanism of action of NAs was not understood until a couple of years ago. Today it is known that upon recognition of NAs, the endolysosomal TLRs and cytosolic sensors activate signalling cascades that culminate in the production of type I IFNs, which primarily include numerous subtypes of IFN-α and a single IFN-β, as well as pro-inflammatory cytokines such as TNF and IL-1β. Type I IFNs then—now acting as DAMPs—induce a vast plethora of antiviral genes through the activation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. Moreover, NAs have been shown to be involved in promoting sterile inflammation upon non-pathogen-mediated traumatic tissue injury [137]. The scenarios are described in more detail in Part VI, Sects. 22.3.3, 22.3.6, and 22.3.7.
2.4.4 Extracellular Histones and Nucleosomes
2.4.4.1 General Remarks
Histones and nucleosomes are critical nuclear proteins that contribute to the structural organization and stability of chromatin. When released from dying cells (succumbing to ACD or RCD such as NETosis) into the extracellular space, histones, that is, free histones and DNA-bound histones (nucleosomes), have been recently recognized as candidates of the DAMP family (for further reading, see Refs. [57, 138,139,140,141,142,143,144]). As known, in eukaryotic cells, DNA is packaged into chromatin, the basic repeating unit of which is a nucleosome. A nucleosome consists of 147 bp nucleotides wrapped around a histone octamer, which is composed of two copies each of histone H2A, H2B, H3, and H4. Nucleosomes are packaged into progressively higher-order structures to form chromosomes ultimately. Notably, unstructured NH2-terminal histone tails that protrude from the nucleosome are subject to covalent chemical modifications, which impact chromatin organization and function (for more details, see Part VI, Sect. 24.2.2, and Fig. 24.1).
2.4.4.2 Binding Step of Histones and Nucleosomes
In in vitro and in vivo studies on TLR2- and TLR4 knockout (KO) mice, extracellular histones were found to induce immunostimulatory signalling in cells such as DCs, ECs, and renal tubular cells as indicated by secretion of TNF, IL-6, and IL-10 [140, 145]. In addition to histone-induced pro-inflammatory innate immune responses via TLR2 and TLR4, subsequent experiments on an in vivo model of hepatic IRI demonstrated that TLR9 KO mice were protected from histone-mediated IRI; these studies encouraged the authors to propose that exogenous histones may have acted as a cofactor that amplified the TLR9-mediated signalling brought about by endogenous circulating DNA released from dying cells [139]. However, as discussed elsewhere [142, 144], these unexpected results might have been influenced by remnant DNA bound to histones, thereby reflecting a DNA → TLR9-dependent DAMP effect.
Notably, as recently discussed by Marsman et al. [142], DNA and histones are organized in nucleosomes in the nucleus, and evidence suggests that nucleosomes are released as such from necrotic cells to exert TLR9-independent immunostimulatory capacities as well. Indeed, nucleosomes have been demonstrated to activate human and murine DCs [146]. Given that nucleosomes were repeatedly found to bind to the plasma membrane, the existence of a nucleosome-specific receptor has been proposed, but this receptor has thus far not been identified. Therefore, further experiments are needed to clarify this unusual phenomenon.
2.4.4.3 Extracellular Function of Histones and Nucleosomes
Besides their immunostimulatory capacities in inducing innate inflammatory responses, extracellular histones were shown to cause direct TLR-independent cytotoxicity to epithelial and endothelial tissue. The exact mechanism of this unique cytotoxic effect is not quite clear. However, current theories suggest that extracellular histone binds to phospholipid–phosphodiester bonds, similar to their DNA-binding sites, an effect that alters membrane permeability and instigates calcium ion influx (reviewed in [144]). As such, extracellular histones have a central role in necroinflammation [147].
Due to their cytotoxic and pro-inflammatory effects, extracellular histones have been shown to contribute to excessive and overwhelming cell damage and death, thus contributing to the pathogenesis of both sepsis and ARDS which may be associated with MOF [148]. More recent findings from experiments in mice reportedly indicate that extracellular histones induce multiple organ injuries in two progressive stages, direct injury to ECs followed by subsequent release of other DAMPs [149]. Besides this acute life-threatening pulmonary event, extracellular histone/nucleosome DAMPs have been shown to be involved in the pathogenesis of various other acute or chronic diseases including cerebral vascular events, myocardial infarction, drug-induced hepatic sterile inflammation, acute kidney injury, and Alzheimer’s disease (reviewed in [144]).
2.4.4.4 Concluding Remarks
In fact, there is an emerging role of histones in their function as DAMPs to mount necroinflammation—as concluded by Silk et al. [144]: “It is clear that both free and DNA-complexed histone have important roles in mediating pro-inflammatory signalling in sterile acute organ injury. Released during periods of cell death and immune activation, histone, nucleosomes and NETs induce cytotoxicity by altering cell membrane permeability to calcium ions, activating TLRs on innate immune cells, stimulating NLRP3 inflammasome and complement systems, resulting in a sterile pro-inflammatory environment. There are three distinct pharmacodynamic approaches to target histone-mediated inflammation, by reducing the release, neutralising or blocking histone signal transduction. Although these approaches have proven to provide significant protection from mortality in animal models of acute organ injury, further research is necessary to warrant their safe application in a clinical setting.”
2.4.5 Nuclear Pro-Forms of Interleukin-1 Family Members
2.4.5.1 Interleukin-33
The DAMP IL-33 is constitutively expressed as a nuclear protein in multiple cell types, in particular, ECs, epithelial cells, and fibroblasts, though its precise function within the nucleus is not fully understood. Nevertheless, IL-33 was found to be able to associate with chromatin by tethering to histones H2A/H2B, via a short chromatin-binding motif, located in its N-terminal nuclear domain [150]. Biologically active full-length IL-33 can be immediately released in the extracellular space after traumatic cell death (necrotic cell death or mechanical injury) enabling instant alarm or danger signalling without the need for further processing or modification (see Refs. [151,152,153,154]). Once released, the cytokine has been reported to operating as a canonical DAMP [155]; regarding this function, other authors denoted IL-33 as an “alarmin” [156] or “dual function-alarmin” [157]). Following emission, IL-33 elicits extracellular effects by binding to the suppressor of tumorigenicity 2 (ST2) receptor (see Part VI, Sect. 22.5.6.4). Although full-length IL-33 is biologically active, cleavage generates mature forms of IL-33 with up to tenfold more biologically active compared to the full-length protein [158].
Of note, IL-33 has been shown to be actively secreted by dying cells or by severely stressed cells, qualifying it as an inducible DAMP (for details, see below, Sect. 14.2.4.2).
2.4.5.2 Interleukin-1alpha Precursor (Pro-Form)
By contrast to the pro-form of IL-1β, the pro-form of IL-1α (= IL-1α precursor/pro-IL-1α) is bioactive and thus operates as a DAMP [159]. The protein is constitutively expressed as an IL-1α precursor in the nuclei of a range of resting non-hematopoietic cells such as EpCs and ECs and in a range of tissues including the lung, liver, and kidney [160] (for more details, see Part VI, Sect. 22.5.6.2). Like IL-33, pro-IL-1α can be immediately released into the extracellular space after necrotic cell death enabling prompt initiation of sterile inflammatory responses without the need for further processing or modification [154, 159]. For example, studies on necrotic cell lysates in mice revealed that IL-1α is a vital DAMP released from necrotic cells to trigger recruitment of neutrophils on neighboring mesothelial cells [161]. These earlier studies were confirmed by studies on necrotic retinal pigment epithelial cells demonstrating IL-1α to trigger pro-inflammatory cytokine and chemokine secretion [162], as well as by more recent experiments showing IL-1α to be released from necrotic corneal epithelial cells, capable of triggering inflammatory responses at the ocular surface [163].
Once extracellular, pro-IL-1α reportedly binds to the IL-1R1 to initiate downstream pro-inflammatory signalling, thereby propagating and extending an inflammatory milieu [164] (see also Part VI, Sect. 22.5.6.2). Of note, in stimulated cells, pro-IL-1α is processed by the membrane-bound protease calpain, before active release as an inducible DAMP into the extracellular space through an unconventional vesicular pathway (for more details, see below, Sect. 14.3.2.2).
2.4.6 Mitochondrial N-Formylated Peptides and Cytochrome C
2.4.6.1 General Remarks
Mitochondria are evolutionary endosymbionts derived from bacteria. Thus, it is not unexpected that they bear molecules as mtDNA and FPs, which were found to be encoded only by bacterial or mitochondrial genes due to initiation of protein synthesis with N-formyl methionine. They are generally cleavage products of bacterial and mitochondrial proteins. Although these peptides play a crucial role in the protein synthesis of bacteria and mitochondria [165], they are not used in cytosolic protein synthesis of eukaryotes. Regardless of their different origin, FPs are known to play a role in the initiation of inflammatory responses by activating the FPRs [166, 167]. In this regard, one may discuss that FPs, like LPS, can operate as both endogenous and exogenous DAMPs (see above, Sect. 11.2.6) (for further reading, see Refs. [168,169,170,171,172]).
2.4.6.2 The Binding Step and Function of N-Formylated Peptides
Formyl peptides are known to bind to FPRs that have been identified as a subfamily of GPCRs (see also Part II, Sect. 5.3.5.3). In human, members include FPR1, FPR2, and FPR3. Through binding with FPRs, FPs serve as potent chemoattractants, which also include activated complements and chemokines, in recruiting and guiding leukocytes to the site of infective and sterile tissue damage. In addition, after binding to FPs, these receptors promote pro-inflammatory responses including cell adhesion, directed migration, granule release, and superoxide production. In recent years, the cellular distribution and biological functions of FPRs have expanded to include additional roles in homeostasis of organ functions and modulation of inflammation (reviewed in [173]).
Earlier studies have already shown that FPs are involved in the pathogenesis of multiple inflammatory diseases such as ulcerative colitis and Crohn’s disease (further reviewed [173]). Recent clinical findings are in support of these early observations showing that the plasma concentration of FPs is increased in trauma patients with SIRS and/or sepsis when compared to control trauma group [11, 167]. In in vitro and in vivo experiments with rats, the investigators observed FPs-induced concentration-dependent contraction in the trachea, bronchi, and bronchioles [172]. Giving these data, the authors concluded that their findings provide a new and different way of considering the role of FPs in acute lung injury and airway contraction following trauma.
2.4.6.3 Role of Cytochrome C as a DAMP
Interestingly, mitochondria-derived cytochrome C has recently been proposed to act as a putative DAMP [171]. In fact, from experimental and clinical studies, cytochrome C is known to be released from dying cells. Evidence in support for a role of cytochrome C as a DAMP was deduced from observations in patients showing that serum cytochrome C levels increase during systemic inflammatory conditions. However, the most convincing proof for this proposal derived from a targeted experimental study showing that in vitro stimulation of murine spleen cells with exogenous cytochrome C results in activation of NF-κB associated with increased production of neutrophil- and monocyte-triggered pro-inflammatory cytokines and chemokines into the culture medium [174]. More recently reported supportive studies on microglia-like cells suggest that the inflammatory effect of cytochrome C is at least partially mediated by TLR4-triggered signalling [175]. Additional studies are required to define cytochrome C as a bona fide DAMP as well as to identify its sensing PRMs precisely.
2.4.6.4 Concluding Remarks
Interestingly, new studies provided evidence proposing the possibility that many so-called cryptides, that is, fragmented peptides derived from various mitochondrial proteins and encoded by mtDNA, may also act as mitochondrial DAMPs to promote sterile inflammation via activation of neutrophils [169]. These observations demonstrate that the story of mitochondrial DAMPs involved in traumatic diseases and sepsis has just begun. For example, the cooperation of mitochondrial FPs with bacterial FPs in case of bacterial sepsis following trauma will become an attractive subject of future clinical SIRS research. In the course of such studies, further mitochondria-derived DAMPs may be discovered and could be considered as putative targets for the treatment of respiratory failure and sterile inflammation.
2.4.7 F-Actin
Another molecule that has recently raised remarkable attention to operating as a DAMP refers to F-actin that was found to trigger sterile inflammation and, in vertebrates, adaptive immunity (comprehensively reviewed by Reis e Sousa’s group in Refs. [176,177,178]). F-actin is an evolutionarily conserved, highly abundant and ubiquitous cytoskeletal protein that usually provides structural support to the cell. In mammals, F-actin is exposed on and released by necrotic cells that have lost plasma membrane integrity to bind to the PRM DNGR-1, a receptor that is expressed selectively by DCs [179]. Like Dectin-1, DNGR-1 is a transmembrane CLR that samples the extracellular and endosomal space and signals via Src and Syk (see Part II, Sect. 5.2.7.3). Following phosphorylation by Src-family kinases, DNGR-1 recruits the tyrosine kinase Syk to promote DC cross-presentation of dead cell-associated antigens.
2.4.8 Heme
Another player in the field of passively released DAMPs refers to red cell-derived heme (for reviews, see [180, 181]). Indeed, a potential role of heme as a DAMP potentially operating in the pathogenesis of transfusion-related acute lung injury (TRALI) was already suggested by Land [182].
The hydrophobic heme is an ancient and ubiquitous molecule present in organisms of all kingdoms, composed of an atom of iron linked to four ligand groups of porphyrin. In situations of hemolysis, large quantities of heme (like other DAMPs such as eATP) are released into the circulation. A high amount of free heme was shown to operate as a potential inducer and amplifier of the inflammatory response. For example, the molecule elicits multiple inflammatory responses, activating leukocytes and their migration, up-regulating adhesion molecule and cytokine expression, and augmenting oxidant production and lipid peroxidation [183,184,185]. Of note, heme, but not porphyrins without iron, was demonstrated to operate as a DAMP promoting the formation of the NLRP3 inflammasome in LPS-primed macrophages [186] (see Part VI, Sect. 22.4.2). Interestingly, in these experiments, the activation of NLRP3 by heme was observed to require spleen tyrosine kinase, NADPH oxidase-2, mitochondrial ROS, and K+ efflux but was independent of heme internalization, lysosomal damage, or ATP release.
In addition, in other lines of studies, heme released in murine sickle cell disease was found to trigger the TLR4-mediated pathway resulting in endothelial cell activation associated with WPB degranulation and vaso-occlusion in murine sickle cell disease [180, 187] (for WPB, see Sect. 14.2.5.3).
In this context, it should not be forgotten that heme acts as an activator of the C3 convertase and thus has been shown to activate complement [188], a topic that will be resumed in Part VI, Sect. 23.2.3.3.
2.4.9 Concluding Remarks
This brief overview is just a snapshot of the world of passively released DAMPs. Some of those molecules have not mentioned here; some others wait for future discovery. It should be noted that the passive release of large amounts of DAMPs is often the consequence of regulated necroptotic cell death that in its own is induced by DAMPs earlier emitted in the course of the injury. The scenario resembles the phenomenon of deadly avalanches when initial local emission of moderate amounts of DAMPs results finally in the generation of large quantities of DAMPs released into the systemic circulation (for more aspects of this phenomenon, compare Part V, Chap. 20).
2.5 DAMPs Indirectly Activating the NLRP3 Inflammasome (Subclass IA-2 DAMPs)
2.5.1 General Remarks
A class of stress-/injury-induced molecules that provide the second signal for activation of the canonical NLRP3 inflammasome is denoted here and throughout both volumes of the book as Class IA-2 DAMPs. As will be outlined in detail in Part VI, Sect. 22.4, inflammasomes are macromolecular protein complexes that are composed of inflammasome-initiating receptors/sensors and inflammatory caspases, in the presence or absence of the inflammasome adapter protein ASC. A typical feature of members of this class of DAMPs is the fact that they do not directly activate inflammasomes via physical binding to NLRP3 but act through the promotion of molecular homeostatic perturbations in an innate immune cell which are then sensed by NLRP3 (compare Part II, Sect. 5.2.3.3). Such DAMPs include eATP at millimolar concentrations, K+ ionophores [189] and crystalline/particulate substances (e.g., MSU, cholesterol crystals, silica, alum), or other factors that cause lysosomal destabilization [190, 191]. As said, these activators are indirectly sensed without direct binding to NLRP3 to trigger inflammasome assembly, IL-1β/IL-18 release, and pyroptosis [192,193,194,195] (for pyroptosis, see Part V, Sect. 19.3.4).
Here, this class of DAMPs is briefly addressed, whereas the activation mechanism of the NLRP3 inflammasome is outlined in more detail in Part VI, Sect. 22.4.
2.5.2 Adenosine-5′-Triphosphate
2.5.2.1 General Remarks
Adenosine-5′-triphosphate can be regarded as the prototype of DAMPs indirectly activating the NLRP3 inflammasome. Like other nucleotides, ATP has both intra-and extracellular functions [196, 197]. Intracellularly, these nucleotides are well known for their function as a universal energy source which drives the biological reactions that allow cells to function and life to flourish. Here, this topic is not further discussed.
2.5.2.2 Passive Release of ATP and the Binding Step
In events of necrosis, ATP is passively released in large quantities. For example, in studies on pressure-disrupted or freeze-thaw-treated necrotic B16 cells, mitochondria-derived ATP was shown to be capable of activating the NLRP3 inflammasome [198]. Once released into the extracellular space, ATP like ADP is rapidly metabolized to adenosine monophosphate (AMP), which in turn is metabolized to adenosine. This nucleotide phosphohydrolysis involves a two-step enzymatic process regulated by ectoenzymes. In the first step, ATP and ADP are both converted to AMP through the ectonucleoside triphosphate diphosphohydrolase 1 (CD39) (reviewed in [199]). To function as a DAMP, eATP initially triggers signalling through the activation of purinergic P2 receptors [200]. As outlined in Part II, Sect. 5.3.4.3, these receptors have a widespread expression throughout different tissues and are involved in innate and adaptive immune responses. As also mentioned in Sect. 5.3.4.3, P2 purinoceptors can be further subdivided into metabotropic P2YRs, which are G-protein-coupled, and ionotropic P2XRs, which are non-selective nucleotide-gated ion channels. Of note, it is the P2X7 receptor through which eATP leads indirectly to canonical NLRP3 activation under involvement of hemichannels of pannexin-1 [192, 194, 201, 202].
2.5.2.3 Extracellular ATP Activates the NLRP3 Inflammasome Indirectly and Functions as a “Find-Me” Signal
In fact, activation of the canonical NLRP3 inflammasome qualifies eATP as a Class IA-2 DAMP. The exact mechanism of this phenomenon is still not fully understood. However, current notions hold that eATP may initially engage P2X7 to change cellular ion composition, in particular, K+ efflux and Ca 2+ influx (detailed in Part VI, Sect. 22.4.2.2).
Besides its role in activating the inflammasome indirectly through P2X7 signalling, eATP-triggered P2Y2R signalling has been identified as a “find-me” signal for leukocytes, promoting phagocytic clearance of apoptotic cells or bacteria by macrophages and neutrophils, thereby contributing to the resolution of inflammation (Fig. 12.4). Other lines of studies have indicated that P2Y2R signalling contributes to fundamental leukocyte functions such as migration and mediator production by neutrophils, eosinophils, DCs, and macrophages (for reviews, see [200, 203]).
2.5.2.4 Concluding Remarks
Together, the dual role of eATP-triggered signalling in both indirect activation of the NLRP3 inflammasome and promotion—as a “find-me” signal—of phagocytic processes confers eATP a unique feature among all members of the DAMP family that may qualify this molecule as a “hybrid DAMP.” Of note, both functions are not executed by eATP after its passive release from necrotic cells alone but also via active secretion by stressed or dying cells; a scenario that will be alluded to below in Sect. 14.2.2.3.
2.5.3 Monosodium Urate Crystals
2.5.3.1 General Remarks
Like ATP, uric acid has been shown to activate the NLRP3 inflammasome indirectly. This molecule is produced when purines, for example, from DNA or RNA, are oxidized by xanthine oxidase, an enzyme found in peroxisomes of most cells. As a regular constituent of healthy cells, where it is believed to possess antioxidant properties, uric acid is released into biological fluids such as blood. In patients suffering from hyperuricaemia as a consequence of too much intake of purines and/or genetic predisposition, uric acid saturates body fluids and may be converted to MSU crystal when deposited in joints and other tissues, thereby causing gout and other inflammatory diseases (reviewed by Rock et al. [204]).
2.5.3.2 Function of Monosodium Urate Crystal as a DAMP
Of note, the biologically active form of uric acid is thought to be crystallized MSU that forms when intracellular stores of uric acid are released into the extracellular environment. In 2003, uric acid was identified by the Rock group as a major DAMP and later on shown in mice to promote an acute inflammatory response when released as crystals from dying cells [205, 206]. Once released into the extracellular space and engulfed by phagocytosing cells such as macrophages, the MSU crystals/particles are sensed by NLRP3 resulting in activation and assembly of the NLRP3 inflammasome. It is suggested that the MSU particles cause the rupture or leakage of lysosomes or phagosomes associated with release of cathepsin B into the cytosol, thereby leading to molecular perturbations of the cell sensed as dyshomeostatic DAMPs by NLRP3 [190, 207, 208]. This process has been known as “frustrated phagocytosis” wherein the phagocytosed crystals cannot be engulfed entirely or digested, thereby leading to changes in the structure of the Golgi complexes like fragmentation and reorganization of Golgi membranes [209]. These perturbations reflect bona fide dyshomeostatic DAMPs which are genuinely sensed by NLRP3. Yet, other mechanisms are also discussed to contribute to NLRP3 activation, such as MSU crystal-promoted K+ efflux reflecting also molecular perturbations that are, as mentioned above, thought to be involved indirectly in ATP sensing (for dyshomeostatic DAMPs, see below, Sect. 13.4.5; for mechanisms of NLRP3 activation, including particulate-mediated activation, see Part VI, Sect. 22.4.2.2).
2.5.3.3 Concluding Remarks
Clearly, via indirect activation of the NLRP3 inflammasome, uric acid represents a potent DAMP capable of inducing inflammatory responses. This implies that in terms of uncontrolled inflammatory pathways, this effect can lead to both acute and chronic inflammatory diseases. As mentioned above, gout disease can be regarded as a classical disorder which can be associated with clinical manifestation of a number of co-morbid conditions including renal disease, hypertension, diabetes mellitus, metabolic syndrome, cardiovascular disease, lipid disorders, and respiratory symptoms (reviewed in [204]). Interestingly, it has been speculated that these comorbidities may pathogenetically be elicited by uric acid in its role as a DAMP—as other DAMPs of this class like cholesterol do, which were shown to contribute to other sterile inflammatory disorders such as atherosclerosis and metabolic syndrome. Future clinical trials will probably give an answer to this burning issue.
Together, uric acid metamorphoses into a potent immunostimulatory DAMP when it undergoes a phase change by nucleating into crystals of MSU that obviously—when ingested by phagocytes as a particle—causes intracellular perturbations to indirectly lead to NLRP3 inflammasome activation. Pathogenetically, the gout disease is regarded as a typical disorder induced via this sketched pathway. Whether or not gout-associated comorbidities are induced by the same path is an interesting speculation but remains to be proven in future clinical trials.
2.5.4 Cholesterol Crystals
2.5.4.1 General Remarks
The phenomenon that irritant crystals/particles can be highly pro-inflammatory is not limited to MSU crystals; indeed, many other crystals and particles operate as “NLRP3-activating DAMPs” to stimulate inflammation and cause disease, such as cholesterol and beta-amyloid (see below), as well as calcium phosphate crystals, alum, crystalline silica, and asbestos [191, 210, 211]. These DAMPs are not released from necrotic cells; instead they use various mechanisms to reach the extracellular space as endogenous DAMPs or as exogenous DAMPs when used as vaccines or inhaled as airborne pollutants.
Here, we focus on cholesterol crystals. Of note, under homeostatic condition, cholesterol biosynthesis, transport, metabolism, and secretion are tightly controlled [212, 213]. Inborn (familiar hypercholesterolemia) or fatty diet-mediated defects in these pathways can result in pathological accumulation of free, unesterified cholesterol in the circulation, which can lead to the formation of toxic cholesterol crystals when nucleated in phagocytic cells or arterial wall [214, 215]. For this scenario, cholesterol is well known to play a critical role in the progression of atherosclerosis that is now regarded as a chronic innate immune inflammatory disease induced by chronic-repetitive infective or sterile injury of the vessel wall. The disorder is further characterized by lipid deposition, leukocyte and macrophage infiltration, and proliferation of VSMCs [216,217,218] (for VSMCs, see Part III, Sect. 9.4.3). The mechanistic role that cholesterol plays in this scenario was not clarified for a long period of time. However, studies during recent years have revealed that its major action can be seen in the activation of the NLRP3 inflammasome.
2.5.4.2 Function of Cholesterol as a DAMP
The first report showing a critical role of the NLRP3 inflammasome in the progression of atherosclerosis was published by Duewell et al. referring to studies on murine macrophages [219]. The authors demonstrated that crystalline cholesterol acts as an endogenous DAMP and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation. Interestingly, these studies also revealed that OxLDL contributes to cholesterol crystallization concomitant with NLRP3 inflammasome priming and activation suggesting that OxLDL may operate as the priming step (signal 1) in NLRP3 assembly (for priming step in NLRP3 activation, see Part VI, Sect. 22.4.2.2). Remarkably, these data were confirmed by other studies on human macrophages demonstrating that cholesterol crystals are able to induce NLRP3 inflammasome activation via lysosomal destabilization [220].
The precise mechanism of how cholesterol crystals are sensed by NLRP3 is not entirely clear. One may again suggest as proposed for MSU and shown by data from human macrophages [220] that these particles after phagocytosis by macrophages induce phagolysosomal destabilization and rupture. As already mentioned above for MSU crystals, the process is known as “frustrated phagocytosis” leading to changes in the structure of the Golgi complexes in terms of like fragmentation and reorganization of Golgi membranes [209]. As intracellular molecular perturbations, these changes reflect bona fide dyshomeostatic DAMPs through which cholesterol is indirectly sensed by NLRP3.
2.5.4.3 Concluding Remarks
At the time being, an increasing number of publications on the role of inflammasomes in atherogenesis can be noticed. Plausibly, cholesterol as an old well-known contributor to this systemic vascular disease has taken center stage. This the more as it has recently become evident that not only innate immune but also adaptive autoimmune processes are involved in the progression of atherosclerosis [221, 222]. This is reason enough to dedicate an own chapter to this topic in Volume 2 of the book.
2.5.5 Lipotoxic Species (Ceramides, Palmitate)
2.5.5.1 General Remarks
The metabolic syndrome (MetS) is a growing public health and clinical challenge worldwide due to escalating urbanization, surplus energy intake, increasing obesity, and sedentary life habits. The syndrome is associated with a fivefold increase in the risk of T2D and twofold the risk of developing cardiovascular disease (CVD) over the forthcoming years [223, 224]. Notably, recent investigations have uncovered a role of the DAMP-activated NLRP3 inflammasome in the pathogenesis of the MetS.
2.5.5.2 Function of Lipotoxic Species
First evidence for a role of DAMPs in obesity-induced inflammation and insulin resistance were reported from studies in mice showing that obesity activates the NLRP3 inflammasome by sensing the lipid molecule ceramide, which is composed from sphingoside and fatty acid [225, 226]. Other lines of studies in rodents confirmed these observations by uncovering further metabolic stress-induced lipid species acting as NLRP3-activating DAMPs. Thus, in a working model in which free fatty acids activate inflammasome-dependent IL-1β secretion from myeloid cells, the investigators found that that elevated fatty acid caused by a high-fat diet was capable of activating the NLRP3 inflammasome in macrophages via a ROS-dependent signalling pathway. Remarkable from these experiments was the observation that IL-1β induced by fatty acid prevents normal insulin signalling in multiple insulin target tissues, ultimately resulting in insulin resistance [227]. Doubtlessly, for clinicians, this finding explicitly explains the development of insulin resistance in obese patients, at least partially. Also, in experiments on murine LPS-treated macrophages, it could be demonstrated that ingested palmitate, a saturated fatty acid ester, activates the NLRP3 inflammasome resulting in a lysosome-dependent release of IL-1β [228]. In their conclusion, the authors also discuss a potential mechanistic role of lysosome destabilization and cathepsin B.
Of note, recent evidence from studies on circulating immune cells of patients with T2D suggests that ceramide- or palmitate-induced ER stress in macrophages may promote upregulation of the ROS → TXNIP axis that is known to contribute to the activation of the NLRP3 inflammasome [229] (for ER stress, see Part V, Sect. 18.5; for ROS → thioredoxin-interacting protein (TXNIP) axis, compare Sect. 13.4.6.3, but also Part VI, Sect. 22.4.2.2).
2.5.5.3 Concluding Remarks
Together, increasing evidence indicates the importance of DAMP-induced activation of the NLRP3 inflammasome in the pathophysiology of MetS. Future intervention studies are expected to reveal whether or not inhibition of NLPR3 inflammasome activation can efficiently prevent the deleterious effects of this metabolic disease.
2.5.6 Beta-Amyloid
Notably, the DAMP Aβ is increasingly discussed to contribute to the pathogenesis of Alzheimer’s and Parkinson’s disease and T2D. Amyloids are proteins with cross-β-sheet structure produced by both bacteria and humans that contribute to pathology and inflammation in complex human diseases, including Alzheimer’s disease, Parkinson’s disease, T2D, and secondary amyloidosis. Pathologically, for example, via Alzheimer’s disease-induced mutations, the membrane-bound amyloid precursor protein (APP) is sequentially cleaved abnormally into a small peptide fragment, Aβ, and secreted into extracellular fluid where they may be highly self-aggregating [230]. Once extracellularly released, the fragments/aggregates operate as an endogenous DAMP.
Today, the pro-inflammatory effects of these proteins are thought to be predominantly mediated by their property to activate the NLRP3 inflammasome. This property was described in an early report by Halle et al. [231], who provided first evidence for a role of Aβ in the pathogenesis of Alzheimer’s disease. Remarkably, already in this early article, the authors suggested that “frustrated phagocytosis” of engulfed Aβ aggregates may contribute to the loss of lysosomal integrity under involvement of the enzyme cathepsin B. Again, today, one may discuss again that, mechanistically, the molecular changes associated with frustrated degradation reflect bona fide dyshomeostatic DAMPs through which Aβ is indirectly sensed by NLRP3.
The increasing relevance of Aβ for the pathogenesis of Alzheimer’s disease is mirrored by a growing list of publications in the international literature (for three examples, see Refs. [230, 232, 233]).
A similar sequela of events is currently discussed for the pathogenesis of Parkinson’s disease. Thus, recent studies showed that amyloid deposits of α-synuclein—known to be the main pathological feature of this disease [234]—induced inflammation through activation of TLR2 and NLRP3 inflammasome only when folded as amyloid fibrils [235].
Also, aggregation of islet Aβ deposits primarily comprised of islet amyloid polypeptide (IAPP) has been found to contribute to beta-cell dysfunction in T2D via upregulation of the NLRP3 inflammasome activation [236,237,238,239]. Interestingly, detailed mechanistic investigations on bone marrow-derived macrophages revealed that IAPP species generated during the early stages of aggregation act as stimuli for TLR2-dependent pro-IL-1β expression, whereas species produced later during aggregation (amyloid fibrils) serve as stimuli for NLRP3-dependent IL-1β secretion reflecting final activation of the inflammasome [238].
2.5.6.1 Concluding Remarks
Intriguingly, it has become apparent that one single DAMP, here Aβ, is involved in several human diseases which at first glance—though all representing chronic inflammatory disorders—have no common pathogenesis and, at least partially, are manifested in different organs. In Volume 2 of the book, the reader will encounter this interesting innate immune phenomenon several times.
2.5.7 Concluding Remarks
It is evident that the subclass of DAMPs described in this section consists of molecules with different structures and functions. The reason for this particularity is reflected by the heading of this section: their property to act as signal 2 necessary to fully activate the canonical NLRP3 inflammasome indirectly. Due to this trait of perturbing the intracellular homeostasis, they are believed to provoke the generation of dyshomeostatic DAMPs which are ultimately sensed by NLRP3 (see below, Sect. 13.4.5). In other words, it is this “double DAMPs axis” that activates the NLRP3 inflammasome to play a leading role in mounting both infective and sterile inflammatory milieus.
2.6 Résumé
The phenomenon of passive release from necrotic cells of a plethora of diverse DAMPs with various pro-inflammatory functions has led to the creation of the new term “necroinflammation.” The remarkable “clou” of this event is that bacterial/viral infection-caused necrosis of cells—via emission of large amounts of endogenous DAMPs—promotes a robust host defense against the virus or the bacterium concerned and not the pathogen per se (for more information about DAMPs as origin and consequences of necroinflammation, see Ref. [50]).
3 DAMPs Exposed at the Cell Surface (Class IB DAMPs)
3.1 Introductory Remarks
The assignment of exposed DAMPs to a separate class is owed to their particularity that they are not passively released from necrotic cells but function as critical DAMPs when exposed at the cell surface, predominantly on stressed or dying cells. In this position, they may carry out entirely different functions. Thus, members of this class of endogenous DAMPs can facilitate phagocytic processes by interacting with scavenger receptors, can activate ILCs and unconventional T cells as ligands for the NKG2D receptor, and can promote cell adhesions in their role as adhesion molecules. Here, in this subchapter, some relevant examples are briefly discussed.
3.2 Phagocytosis-Facilitating Molecules (“Chaperones”) (Subclass IB-1 DAMPs)
3.2.1 General Remarks
Phagocytosis-facilitating molecules in terms of chaperones can operate as DAMPs exposed at the plasma membrane via promotion of engulfment of antigenic material by phagocytes such as DCs. In fact, such DAMPs can be considered to be capable of “scanning” the antigenic pattern of stressed or dying cells such as cancer cells on encountering processed antigenic peptides. These DAMPs subsequently meet professional phagocytes such as DCs and macrophages, where they are recognized as “eat-me” signals by scavenger receptors, for example, by the scavenger receptor CD91 (also called the LDL-receptor-related protein 1 or LRP1) that has recently gained special attention as an important receptor on DCs to facilitate engulfment of antigens (compare Part II, Sect. 5.3.3; and for reviews, see Refs. [240,241,242,243]). Of note, another “eat-me” signal is lysophosphatidylserine that acts as an inducible inflammation-resolving DAMP and will be described below in Sect. 14.4.5.
3.2.2 Calreticulin
3.2.2.1 General Remarks
A crucial Class IB-1 DAMP recognized by CD91 is CALR, an ER-based chaperone that when outside of the ER as “ecto-CALR” has emerged to exert an explosion of crucial functions from the cell surface and extracellular environment [244, 245].
Calreticulin—as an “eat-me” signal for phagocytes—is a member of immunogenic HSPs family. The protein is a highly conserved, ER-resided, Ca2+-binding chaperone protein that plays a key role in the activity and regulation of Ca2+ homeostasis/signalling, and through the interaction with the isomerase ERp57 (= a protein disulfide isomerase that catalyzes disulfide bonds formation of glycoproteins as part of the calnexin and calreticulin cycle), CALR facilitates proper folding of ER-chaperoned proteins (reviewed in [246]). The molecule also contributes to the correct assembly of MHC-I molecules and insures efficient loading of antigens [247].
Of note, when stressing insults provoke ER stress, the serine/threonine kinase PERK becomes activated and phosphorylates eIF2α to elicit a UPR that—when unsuccessful—results in apoptotic cell death (for details of UPR, see Part V, Sect. 18.5). In the course of the UPR, before completion of apoptosis, the complex CALR/ERp57 is translocated to the plasma membrane to get exposed (Fig. 12.5). Importantly, both the action of PERK and the phosphorylation of eIF2α are required for this translocation. In addition, CALR/ERp57 appears on the surface of stressed, mostly apoptotically dying cells as a result of exocytosis, following a classical pathway in which Golgi apparatus-derived vesicles fuse with the plasma membrane in a SNARE-dependent manner (for details, see Ref. [248]).
3.2.2.2 Extracellular Functions of Calreticulin and Its Cognate Binding Receptors
Calreticulin when outside of the ER and translocated to the plasma membrane (now called ecto-CALR) exerts multiple functions and plays a critical role in the phagocytic removal of apoptotic cells. With respect to this function, surface-exposed CALR acts as a DAMP on apoptotic cells, thereby generating an engulfment signal that stimulates the uptake of apoptotic corpses and the presentation/cross-presentation of the corresponding antigens by DCs (reviewed in Refs. [249,250,251]) (for antigen presentation and cross-presentation by DCs, see Part VIII, Sects. 31.3.4 and 31.3.5). This scenario plays an eminent role in engulfment of tumor-associated antigens (TAAs) that—via the process of ICD—contributes to a vigorous anti-tumor immune response [252].
The phagocytosis-facilitating function is mainly executed through binding and activation of the CD91 receptor on the phagocytes [249] (compare Part II, Sect. 5.3.3.3). Importantly, it is this receptor on DCs which allows for cross-priming/cross-presentation of the chaperoned peptide antigen [253]. This action is of immense relevance for cross-presentation of TAAs.
Notably, the CD91 receptor is a transmembrane protein, acting as a co-receptor for the bridging molecule opsonin C1q, a complement component. Hence, CALR together with CD91 is critically essential for C1q-mediated phagocytosis of opsonized pathogens and apoptotic bodies. Moreover, besides CD91 and C1q, some other CALR’s partners are critical in modulating the whole phagocytosing process including bridging or/and signalling molecules phosphatidylserine (PS; “eat-me” signal) (Fig. 12.5), CD47 (“don’t eat-me” signal), and the scavenger receptor SRF-I (also called SREC-I or SCARF1) (reviewed in [254]) (for SRF-1, also see Part II, Sect. 5.3.3.2; for C1q see Part VI, Sect. 23.2.2.2).
It is worth adding here that CALR was found to be actively secreted by cancer cells to act as a soluble DAMP. Thus, clinical studies in patients suffering from RA, SLE, and lung cancer showed that CALR in its soluble form circulates in the periphery, in lung cancer patients before and—in much higher concentration—after chemotherapy. As such, the DAMP was proposed to use clinically as a potential diagnostic biomarker in lung cancer patients [255]. Subsequent studies of the same group provided evidence suggesting the scavenger receptor SRA to sense the soluble form of CALR, thereby triggering macrophage activation [256].
3.2.2.3 Concluding Remarks
There is emerging evidence suggesting a critical role of CALR in inducing increased immunogenicity in cancer cells. As mentioned above, the DAMP serves as a phagocytic signal on cancer cells following induction of ICD, thereby contributing to the maturation of immunogenic DCs, which elicit—via efficient cross-presentation of TAAs—a potent anti-tumor CD8+ T cell response. This scenario makes tumors susceptible to immunotherapy-based anticancer strategies. For this reason, CALR is now regarded as one of the most potent target DAMPs for developing new anticancer therapeutics (more details of ICD will be presented in Volume 2).
3.2.3 Heat Shock Proteins as DAMPs Exposed at the Cell Surface
Heat shock proteins operate as DAMPs when passively released or actively secreted into the extracellular space (see above, Sect. 12.2.3, and below Sect. 14.2.2). Like CALR, HSPs can also be exposed at the cell membrane. At this position, they are known to support engulfment of antigenic peptides by phagocytosing cells, whereby CD91 also serves as the key endocytic receptor. For example, HSP70 is considered to “sample” the antigenic milieu of cancer cells on encountering processed peptides in vivo and can be used to carry this sample into the APC during immunization [90]. Similarly, HSP70 and HSP60 exposed on stressed apoptotic cells were found to increase their immunogenicity, thereby generating a T cell-mediated specific anti-tumor response [257]. In other lines of studies, severe heat shock-treated cancer cells were shown to expose, besides CALR, HSP70 and HSP90, thereby contributing to immunogenicity of a tumor [258]. Again, like the interaction of CALR with CD91, the HSP70 → CD91 axis was shown to be required for cross-presentation of HSP-chaperoned peptides to elicit a potent anti-tumor immune response (reviewed in [253]).
3.2.3.1 Concluding Remarks
Together, these findings show that HSPs in their role as chaperones for antigenic peptides can function as strong DAMPs to facilitate engulfment of antigenic peptides, for example, derived from TAAs. It is for this reason that tumor-derived HSPs have been proposed to use for anticancer immunotherapy [259].
3.2.4 Concluding Remarks
Molecules such as CALR and HSPs, for example, expressed on tumor cells, can function as endocytosis-promoting DAMPs by facilitating engulfment of antigenic peptides recognized by cognate PRMs such as CD91 and TLRs. As already mentioned, this phenomenon, that is, HSPs complexed with antigenic peptides, is currently being used to prepare effective vaccines in virology and oncology to elicit strong antiviral and anti-tumor immunity [260, 261]. Calreticulin is of special importance because it has been demonstrated to act as a mandatory DAMP to increase immunogenicity of cancer cells via the phenomenon of ICD. In Volume 2, the important function of the ER-associated chaperones CALR and HSPs will be resumed in their role as DAMPs to fight against cancer growth.
3.3 Major Histocompatibility Class I Chain-Related Molecules (Subclass IB-2 DAMPs)
3.3.1 General Remarks
Another class of DAMPs which exert their function as danger signals when exposed on the cell plasma membrane refers to molecules here sorted into IB-2 DAMPs. Though these DAMPs are characterized by numerous and highly variable genetic, structural, and biochemical features, they all belong to the major histocompatibility complex Class I gene superfamily (MHC-I-related proteins) and bind to a single, invariant, receptor, the NKG2D receptor (compare Part II, Sect. 5.3.7.4). This activating receptor is expressed on the surface of NK cells, iNKT, γδ T cells, CD8+ MAIT, CD8+ T cells, and subsets of CD4+ T cells (compare Part VII, Sects. 27.2.2, 28.2.2, and 28.4.2). The receptor NKG2D serves as a major recognition receptor for this class of DAMPs to detect and eliminate cells, which are stressed as transformed or infectively and sterilely damaged cells. On healthy cells, these endogenous IB-2 DAMPs (also called NKG2D ligands) are expressed at a low level only, but their expression is markedly induced on such stressed cells, whereby they translocate (probably from the stressed ER [262]) to the plasma membrane to get anchored and exposed.
Two families of IB-2 DAMPs, mainly expressed on epithelial cells and ECs, have been identified in humans: (1) the stress-inducible molecules non-conventional MICA and MICB, which could be considered prototypical members of this class, and (2) the stress-inducible UL16 binding proteins 1, 2, and 3 (ULBPs 1, 2, 3), together with two novel members of this family, the ULBP/retinoic acid early inducible protein 1 (RAET1) gene cluster, ULBP4/RAET1E and ULBP4/RAET1G (for reviews, see Refs. [263,264,265,266,267,268,269]).
Of note, among these danger signals, MICA and MICB are the most polymorphic. To date, 100 alleles are known for MICA and 40 for MICB. This corresponds to 79 and 26 unique protein sequences, respectively. Although these numbers are far smaller than those for classical HLA Class I molecules (close to 10,000 alleles and 7000 proteins), one has to bear in mind that our current knowledge of HLA diversity spans from genotyping of over 20 million individuals (current estimate of the size of international bone marrow registries) (competently reviewed by Carapito and Bahram [263]). The proteins ULBP/RAET1 seem to be less polymorphic than MICs. This may be due, however, to sampling, as fewer than 300 individuals have been sequenced. Among the six ULBP/RAET1 genes, four have been found to be polymorphic in exon 2 and exon 3 coding for the a1 and a2 domains, respectively [263].
3.3.2 Regulation of MHC-I Chain-Related Molecules
Mechanisms of regulation of members of this subclass of DAMPs have been comprehensively reviewed by Raulet et al. [270]. Cell stress stimuli induce generation of these DAMPs, which are regulated at several levels of biogenesis by various types of such signals that are worked out in distressed, infected, or transformed cells. The regulatory processes have been found to occur discerned at the transcriptional, post-transcriptional, translational, and post-translational levels. The signals that regulate the various steps of DAMP biogenesis are induced in the course of stress responses such as the oxidative stress response, the heat shock response (HSR), the DDR, and the ER stress-initiated UPR (for these stress responses, see Part V, Sects. 18.3–18.6). Thus, in a way and broader sense, they can be also regarded as DAMPs. For example, in the case of cancer, numerous independent pathways such as the DDR and the UPR (under involvement of transcription factor E2F) that are activated in proliferating cancer cells are likely to collaborate in the induction of DAMPs (for E2F, see Box 12.1). In case of infective cell injury, the HSR pathway, at least in part, has been shown to play a role in the induction of MICA and MICB at the transcriptional level. Moreover, there is some evidence suggesting that (DAMP?) → TLR-triggered activation of the transcription factors TBK1 and IRF3 is implicated in the production of these DAMPs. Sterile cell injury, such as oxidative stress, can also induce the generation of IB-2 DAMPs, although little is known concerning the underlying mechanisms. Nevertheless, there is some evidence suggesting that the DAMP OxLDL (see below, Sect. 13.3.2) sensed by TLR4 is involved in generation of members of this class of DAMPs at the transcriptional level (mostly reviewed in [270]).
Box 12.1 What About E2F factors?
E2F is a group of genes that codifies a family of transcription factors (TF) in higher eukaryotes. Three of them are activators: E2F1, E2F2, and E2F3a. Six others act as suppressors: E2F3b, E2F4-8. All of them are involved in cell-cycle regulation and synthesis of DNA in mammalian cells. E2Fs as TFs bind to the TTTCGCGC consensus binding site in the target promoter sequence of genes.
Further reading: Dimova DK, Dyson NJ. The E2F transcriptional network: old acquaintances with new faces. Oncogene 2005;24:2810–26.
Finally, the newly, in the course of stress responses, generated molecules translocate through the cytosol via the ER and the Golgi apparatus to become anchored on the plasma membrane. In addition to exposure, the DAMPs can also be secreted, or excreted in vesicles such as exosomes, or shed via proteolytic cleavage. In this case, the molecules may interact with NKG2D on the surface of NK cells and unconventional T cells, thereby blocking the receptors on these cells in a manner that inhibits their interactions with target cells resulting in reduced cytotoxicity (reviewed also in [270]).
3.3.3 Function of MHC-I Chain-Related Molecules
This subclass of DAMPs is critical for the activation of NKG2D-expressing cells that execute killing activities; they include ILCs such as NK cells and unconventional T cells such as iNKT, CD8+MAIT, and γδ T cells (see Part III, Sects. 8.4.3.3 and 8.5.2–8.5.4; as well as Part VII, Sects. 27.2.2, 28.2.2, 28.3.2, and 28.4.2). For further details of the function of these cells in viral infections and tumor cell surveillance, the reader is referred to these sections.
3.3.4 Concluding Remarks
The subclass of DAMPs briefly addressed in this section play an increasing role in viral infections and tumor growth. Regarding the many possibilities of which viruses and tumors have devised mechanisms to evade detection and elimination by NKG2D-bearing killing cells, therapeutic strategies are considered to restore or enhance NKG2D-dependent activation of these cells, in particular, NK cells. On the other hand—as splendidly outlined by Lanier [264]—where DAMP-activated NKG2D-bearing cells contribute to aggravate autoimmune responses, suppression of expression of these DAMPs in inflammation provides an attractive therapeutic target. As concluded by Lanier [264], “A better understanding of the cell-intrinsic and -extrinsic mechanisms that regulate the expression of the NKG2D ligands and the intracellular signals controlling NKG2D-induced responses in T cells and NK cells is needed to take full advantage of this potent immune pathway.”
3.4 Résumé
It becomes apparent to the reader that the molecules sorted in this subchapter possess different structures, different locations, and various functions. Indeed, one could classify them in their role as DAMPs choosing other ways. The common feature here chosen is their exposure on the cell surface, though some of them have been shown to be secreted as well. The critical role of Subclass IB-1 DAMPs is their function in facilitating antigen uptake. For example, CALR, as mentioned, has a vital impact on engulfment of TAAs to increase the immunogenicity of cancer cells via the phenomenon of ICD. On the other hand, MICS, here MICA, have gained center stage by documenting that it has the requisite attributes of a bona fide transplantation antigen. Thus, recent studies by Carapito et al. showed that matching for the non-conventional MHC-I MICA gene significantly reduces the incidence of acute and chronic graft-versus-host disease (GVHD) [271]. The authors concluded from their findings—besides others—that “The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice.”
4 Outlook
Certainly, the list of endogenous constitutively expressed native DAMPs as selected and presented in this chapter refers to the more prominent DAMPs and thus is not complete. Of particular importance are the Class IA DAMPs because, as native molecules passively released from necrotic cells, they are now known to promote necroinflammatory responses (reviewed by Sarhan et al. in Ref. [50]). In fact, the phenomenon of necroinflammation as a common consequence of necrosis, in particular, RN such as necroptosis and ferroptosis, gains increasing attention, and growing evidence suggests a significant in vivo impact on human diseases [272, 273]. The authors conclude “that targeting regulated necrosis in vivo represents a novel concept that requires the establishment of first-in-class compounds for clinical use.”
Compared to Class IA DAMPs, Class IB DAMPs have been neglected for a while. On the other hand, as mentioned, they are now recognized as DAMPs, which are emitted by stressed but not necessarily dying cells. As such, these DAMPs may take over an important innate immune defending function together with damage-modified molecules (Cat. II DAMPs) in moderately stressful situations, in which no necrotic cell death occurs.
Together, endogenous constitutively expressed native molecules represent an impressive category of DAMPs with extraordinary properties. In Volume 2, their negative, detrimental role in the pathogenesis of many human diseases will be thoroughly outlined.
References
Seong S-Y, Matzinger P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol. 2004;4:469–78. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15173835
Land WG. Emerging role of innate immunity in organ transplantation part II: potential of damage-associated molecular patterns to generate immunostimulatory dendritic cells. Transplant Rev (Orlando). 2012;26:73–87. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22074784
Tang D, Kang R, Zeh HJ, Lotze MT. High-mobility group box 1, oxidative stress, and disease. Antioxid Redox Signal. 2011;14:1315–35. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20969478
Tsung A, Tohme S, Billiar TR. High-mobility group box-1 in sterile inflammation. J Intern Med. 2014;276:425–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24935761
Asea A. Heat shock proteins and toll-like receptors. Handb Exp Pharmacol. 2008;183:111–27. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18071657
Land WG. Role of heat shock protein 70 in innate alloimmunity. Front Immunol. 2011;2:89. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22566878
Miyake Y, Yamasaki S. Sensing necrotic cells. Adv Exp Med Biol. 2012;738:144–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22399378
Schiopu A, Cotoi OS. S100A8 and S100A9: DAMPs at the crossroads between innate immunity, traditional risk factors, and cardiovascular disease. Mediators Inflamm. 2013;2013:828354. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24453429
Pruenster M, Vogl T, Roth J, Sperandio M. S100A8/A9: from basic science to clinical application. Pharmacol Ther. 2016.; Available from: http://www.ncbi.nlm.nih.gov/pubmed/27492899
Jounai N, Kobiyama K, Takeshita F, Ishii KJ. Recognition of damage-associated molecular patterns related to nucleic acids during inflammation and vaccination. Front Cell Infect Microbiol. 2012;2:168. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23316484
Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20203610
Pardo M, Budick-Harmelin N, Tirosh B, Tirosh O. Antioxidant defense in hepatic ischemia-reperfusion injury is regulated by damage-associated molecular pattern signal molecules. Free Radic Biol Med. 2008;45:1073–83. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18675899
Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11:373–84. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20404851
Hansen JD, Vojtech LN, Laing KJ. Sensing disease and danger: a survey of vertebrate PRRs and their origins. Dev Comp Immunol. 2011;35:886–97. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21241729
Drummond RA, Brown GD. Signalling C-type lectins in antimicrobial immunity. PLoS Pathog. 2013;e1003417:9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23935480
Lee EJ, Park JH. Receptor for advanced glycation endproducts (RAGE), its ligands, and soluble RAGE: potential biomarkers for diagnosis and therapeutic targets for human renal diseases. Genomics Inform. 2013;11:224–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24465234
Ratsimandresy RA, Dorfleutner A, Stehlik C. An update on PYRIN domain-containing pattern recognition receptors: from immunity to pathology. Front Immunol. 2013;4:440. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24367371
Unterholzner L. The interferon response to intracellular DNA: why so many receptors? Immunobiology. 2013;218:1312–21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23962476
Zhong Y, Kinio A, Saleh M. Functions of NOD-like receptors in human diseases. Front Immunol. 2013;4:333. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24137163
Alessandra P, Sergio C. NOD-like receptors: a tail from plants to mammals through invertebrates. Curr Protein Pept Sci. 2016.; Available from: http://www.ncbi.nlm.nih.gov/pubmed/26983790
Sohn J, Hur S. Filament assemblies in foreign nucleic acid sensors. Curr Opin Struct Biol. 2016;37:134–44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26859869
Portou MJJ, Baker D, Abraham D, Tsui J. The innate immune system, toll-like receptors and dermal wound healing: a review. Vascul Pharmacol. 2015;71:31–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25869514
Campana L, Santarella F, Esposito A, Maugeri N, Rigamonti E, Monno A, et al. Leukocyte HMGB1 is required for vessel remodeling in regenerating muscles. J Immunol. 2014;192:5257–64. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24752445
Turner NA. Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs). J Mol Cell Cardiol. 2016;94:189–200. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26542796
Anders H-J, Schaefer L. Beyond tissue injury-damage-associated molecular patterns, toll-like receptors, and inflammasomes also drive regeneration and fibrosis. J Am Soc Nephrol. 2014;25:1387–400. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24762401
Nakagawa S, Omura T, Yonezawa A, Yano I, Nakagawa T, Matsubara K. Extracellular nucleotides from dying cells act as molecular signals to promote wound repair in renal tubular injury. Am J Physiol Renal Physiol. 2014;307:F1404–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25354940
Zhang W, Lavine KJ, Epelman S, Evans SA, Weinheimer CJ, Barger PM, et al. Necrotic myocardial cells release damage-associated molecular patterns that provoke fibroblast activation in vitro and trigger myocardial inflammation and fibrosis in vivo. J Am Heart Assoc. 2015;4:e001993. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26037082
Land W. Allograft injury mediated by reactive oxygen species: from conserved proteins of drosophila to acute and chronic rejection of human transplants. Part III: interaction of (oxidative) stress-induced heat shock proteins with toll-like receptor-bearing cells. Transplant Rev. 2003;17:67–86. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0955470X0380006X
Goodwin GH, Sanders C, Johns EW. A new group of chromatin-associated proteins with a high content of acidic and basic amino acids. Eur J Biochem. 1973;38:14–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/4774120
Bianchi ME, Manfredi AA. High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol Rev. 2007;220:35–46. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17979838
Vénéreau E, Ceriotti C, Bianchi ME. DAMPs from cell death to new life. Front Immunol. 2015;6:422. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26347745
Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418:191–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12110890
Bianchi ME, Agresti A. HMG proteins: dynamic players in gene regulation and differentiation. Curr Opin Genet Dev. 2005;15:496–506. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0959437X05001371
Lu B, Wang C, Wang M, Li W, Chen F, Tracey KJ, et al. Molecular mechanism and therapeutic modulation of high mobility group box 1 release and action: an updated review. Expert Rev Clin Immunol. 2014;10:713–27. Available from: http://www.tandfonline.com/doi/full/10.1586/1744666X.2014.909730
Lotze MT, Zeh HJ, Rubartelli A, Sparvero LJ, Amoscato AA, Washburn NR, et al. The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunol Rev. 2007;220:60–81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17979840
Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L, et al. HMGB1 in health and disease. Mol Aspects Med. 2014;40:1–116. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25010388
Klune JR, Dhupar R, Cardinal J, Billiar TR, Tsung A. HMGB1: endogenous danger signaling. Mol Med. 2008;14:476–84. Available from: http://www.molmed.org/content/pdfstore/476_484.Klune.00034.PDF
Malarkey CS, Churchill MEA. The high mobility group box: the ultimate utility player of a cell. Trends Biochem Sci. 2012;37:553–62. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0968000412001430
Andersson U, Erlandsson-Harris H, Yang H, Tracey KJ. HMGB1 as a DNA-binding cytokine. J Leukoc Biol. 2002;72:1084–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12488489
Wang Q, Zeng M, Wang W, Tang J. The HMGB1 acidic tail regulates HMGB1 DNA binding specificity by a unique mechanism. Biochem Biophys Res Commun. 2007;360:14–9. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0006291X07011242
Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol. 2011;29:139–62. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21219181
Sánchez-Giraldo R, Acosta-Reyes FJ, Malarkey CS, Saperas N, Churchill MEA, Campos JL. Two high-mobility group box domains act together to underwind and kink DNA. Acta Crystallogr D Biol Crystallogr. 2015;71:1423–32. Available from: http://scripts.iucr.org/cgi-bin/paper?S1399004715007452
Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci U S A. 2004;101:296–301. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.2434651100
Palumbo R, De Marchis F, Pusterla T, Conti A, Alessio M, Bianchi ME. Src family kinases are necessary for cell migration induced by extracellular HMGB1. J Leukoc Biol. 2009;86:617–23. Available from: http://www.jleukbio.org/cgi/doi/10.1189/jlb.0908581
Venereau E, Casalgrandi M, Schiraldi M, Antoine DJ, Cattaneo A, De Marchis F, et al. Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J Exp Med. 2012;209:1519–28. Available from: http://www.jem.org/lookup/doi/10.1084/jem.20120189
Beyer C, Pisetsky DS. Modeling nuclear molecule release during in vitro cell death. Autoimmunity. 2013;46:298–301. Available from: http://www.tandfonline.com/doi/full/10.3109/08916934.2012.750297
Tang D, Shi Y, Kang R, Li T, Xiao W, Wang H, et al. Hydrogen peroxide stimulates macrophages and monocytes to actively release HMGB1. J Leukoc Biol. 2007;81:741–7. Available from: http://www.jleukbio.org/cgi/doi/10.1189/jlb.0806540
Kaczmarek A, Vandenabeele P, Krysko DV. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity. 2013;38:209–23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23438821
Magna M, Pisetsky DS. The role of HMGB1 in the pathogenesis of inflammatory and autoimmune diseases. Mol Med. 2014;20:138–46. Available from: http://www.molmed.org/content/pdfstore/13_164_Magna.pdf
Sarhan M, Land WG, Tonnus W, Hugo CP, Linkermann A. Origin and consequences of necroinflammation. Physiol Rev. 2018;98(2):727–80. https://doi.org/10.1152/physrev.00041.2016
Linkermann A. Nonapoptotic cell death in acute kidney injury and transplantation. Kidney Int. 2016;89:46–57. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26759047
Tsung A, Sahai R, Tanaka H, Nakao A, Fink MP, Lotze MT, et al. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med. 2005;201:1135–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15795240
Andrassy M, Volz HC, Igwe JC, Funke B, Eichberger SN, Kaya Z, et al. High-mobility group box-1 in ischemia-reperfusion injury of the heart. Circulation. 2008;117:3216–26. Available from: http://circ.ahajournals.org/cgi/doi/10.1161/CIRCULATIONAHA.108.769331
Cohen MJ, Brohi K, Calfee CS, Rahn P, Chesebro BB, Christiaans SC, et al. Early release of high mobility group box nuclear protein 1 after severe trauma in humans: role of injury severity and tissue hypoperfusion. Crit Care. 2009;13:R174. Available from: http://ccforum.biomedcentral.com/articles/10.1186/cc8152
Peltz ED, Moore EE, Eckels PC, Damle SS, Tsuruta Y, Johnson JL, et al. HMGB1 is markedly elevated within 6 hours of mechanical trauma in humans. Shock. 2009;32:17–22. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19533845
Denk S, Weckbach S. Eisele P. Wiegner R, Ohmann JJ, et al. Role of Hemorrhagic Shock in Experimental Polytrauma. Shock: Braun CK; 2017. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28614141
Yang R, Zou X, Tenhunen J, Tønnessen TI. HMGB1 and extracellular histones significantly contribute to systemic inflammation and multiple organ failure in acute liver failure. Mediators Inflamm. 2017;2017:1–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28694564
Zhou R-R, Liu H-B, Peng J-P, Huang Y, Li N, Xiao M-F, et al. High mobility group box chromosomal protein 1 in acute-on-chronic liver failure patients and mice with ConA-induced acute liver injury. Exp Mol Pathol. 2012;93:213–9. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0014480012000834
Seo YS, Kwon JH, Yaqoob U, Yang L, De Assuncao TM, Simonetto DA, et al. HMGB1 recruits hepatic stellate cells and liver endothelial cells to sites of ethanol-induced parenchymal cell injury. Am J Physiol Gastrointest Liver Physiol. 2013;305:G838–48. Available from: http://ajpgi.physiology.org/cgi/doi/10.1152/ajpgi.00151.2013
Wang H, Ward MF, Fan X-G, Sama AE, Li W. Potential role of high mobility group box 1 in viral infectious diseases. Viral Immunol. 2006;19:3–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16553546
Zheng W, Shi H, Chen Y, Xu Z, Chen J, Jin L. Alteration of serum high-mobility group protein 1 (HMGB1) levels in children with enterovirus 71-induced hand, foot, and mouth disease. Medicine (Baltimore). 2017;96:e6764. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28445307
Resman Rus K, Fajs L, Korva M, Avšič-Županc T. HMGB1 is a potential biomarker for severe viral hemorrhagic fevers. PLoS Negl Trop Dis. 2016;e0004804:10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27348219
Parkkinen J, Raulo E, Merenmies J, Nolo R, Kajander EO, Baumann M, et al. Amphoterin, the 30-kDa protein in a family of HMG1-type polypeptides. Enhanced expression in transformed cells, leading edge localization, and interactions with plasminogen activation. J Biol Chem. 1993;268:19726–38. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8366113
Kokkola R, Andersson A, Mullins G, Ostberg T, Treutiger C-J, Arnold B, et al. RAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophages. Scand. J Immunol. 2005;61:1–9. Available from: http://doi.wiley.com/10.1111/j.0300-9475.2005.01534.x
Fiuza C, Bustin M, Talwar S, Tropea M, Gerstenberger E, Shelhamer JH, et al. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood. 2003;101:2652–60. Available from: http://www.bloodjournal.org/cgi/doi/10.1182/blood-2002-05-1300
Schiraldi M, Raucci A, Muñoz LM, Livoti E, Celona B, Venereau E, et al. HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4. J Exp Med. 2012;209:551–63. Available from: http://www.jem.org/lookup/doi/10.1084/jem.20111739
Park JS, Svetkauskaite D, He Q, Kim J-Y, Strassheim D, Ishizaka A, et al. Involvement of Toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem. 2004;279:7370–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14660645
Tsung A, Hoffman RA, Izuishi K, Critchlow ND, Nakao A, Chan MH, et al. Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells. J Immunol. 2005;175:7661–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16301676
Urbonaviciute V, Fürnrohr BG, Meister S, Munoz L, Heyder P, De Marchis F, et al. Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J Exp Med. 2008;205:3007–18. Available from: http://www.jem.org/lookup/doi/10.1084/jem.20081165
Tian J, Avalos AM, Mao S-Y, Chen B, Senthil K, Wu H, et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol. 2007;8:487–96. Available from: http://www.nature.com/doifinder/10.1038/ni1457
Ivanov S, Dragoi A-M, Wang X, Dallacosta C, Louten J, Musco G, et al. A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA. Blood. 2007;110:1970–81. Available from: http://www.bloodjournal.org/cgi/doi/10.1182/blood-2006-09-044776
Youn JH, Oh YJ, Kim ES, Choi JE, Shin J-S. High mobility group box 1 protein binding to lipopolysaccharide facilitates transfer of lipopolysaccharide to CD14 and enhances lipopolysaccharide-mediated TNF-alpha production in human monocytes. J Immunol. 2008;180:5067–74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18354232
Yanai H, Ban T, Wang Z, Choi MK, Kawamura T, Negishi H, et al. HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature. 2009;462:99–103. Available from: http://www.nature.com/doifinder/10.1038/nature08512
Antoine DJ, Harris HE, Andersson U, Tracey KJ, Bianchi ME. A systematic nomenclature for the redox states of high mobility group box (HMGB) proteins. Mol Med. 2014;20:135–7. Available from: http://www.molmed.org/content/pdfstore/14_022_Antoine.pdf
Yang H, Wang H, Ju Z, Ragab AA, Lundbäck P, Long W, et al. MD-2 is required for disulfide HMGB1-dependent TLR4 signaling. J Exp Med. 2015;212:5–14. Available from: http://www.jem.org/lookup/doi/10.1084/jem.20141318
Agalave NM, Larsson M, Abdelmoaty S, Su J, Baharpoor A, Lundbäck P, et al. Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis. Pain. 2014;155:1802–13. Available from: http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00006396-201409000-00016
Štros M. HMGB proteins: interactions with DNA and chromatin. Biochim Biophys Acta Gene Regul Mech. 2010;1799:101–13. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20123072
Hoppe G, Talcott KE, Bhattacharya SK, Crabb JW, Sears JE. Molecular basis for the redox control of nuclear transport of the structural chromatin protein Hmgb1. Exp Cell Res. 2006;312:3526–38. Available from: http://linkinghub.elsevier.com/retrieve/pii/S001448270600303X
Garg AD, Agostinis P. Cell death and immunity in cancer: from danger signals to mimicry of pathogen defense responses. Immunol Rev. 2017;280:126–48. Available from: http://doi.wiley.com/10.1111/imr.12574
Yang D, de la Rosa G, Tewary P, Oppenheim JJ. Alarmins link neutrophils and dendritic cells. Trends Immunol. 2009;30:531–7. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1471490609001422
Lindquist S, Craig EA. The heat-shock proteins. Annu Rev Genet. 1988;22:631–77. Available from: http://www.annualreviews.org/doi/10.1146/annurev.ge.22.120188.003215
Ritossa F. A new puffing pattern induced by heat shock and DNP in Drosophila. Experientia. 1962;18:571–3.
Tissières A, Mitchell HK, Tracy UM. Protein synthesis in salivary glands of Drosophila melanogaster: relation to chromosome puffs. J Mol Biol. 1974;84:389–98. Available from: http://www.ncbi.nlm.nih.gov/pubmed/4219221
Michaud S, Marin R, Tanguay RM. Regulation of heat shock gene induction and expression during Drosophila development. Cell Mol Life Sci. 1997;53:104–13. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9117990
Javid B, MacAry PA, Lehner PJ. Structure and function: heat shock proteins and adaptive immunity. J Immunol. 2007;179:2035–40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17675458
Gallucci S, Lolkema M, Matzinger P. Natural adjuvants: endogenous activators of dendritic cells. Nat Med. 1999;5:1249–55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10545990
Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol. 2000;12:1539–46. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11058573
El Mezayen R, El Gazzar M, Seeds MC, McCall CE, Dreskin SC, Nicolls MR. Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin. Immunol Lett. 2007;111:36–44. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0165247807001010
Mambula SS, Calderwood SK. Heat induced release of Hsp70 from prostate carcinoma cells involves both active secretion and passive release from necrotic cells. Int J Hyperthermia. 2006;22:575–85. Available from: http://www.tandfonline.com/doi/full/10.1080/02656730600976042
Calderwood SK, Gong J, Murshid A. Extracellular HSPs: the complicated roles of extracellular HSPs in immunity. Front Immunol. 2016;7:159. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27199984
Asea A. Initiation of the immune response by extracellular Hsp72: chaperokine activity of Hsp72. Curr Immunol Rev. 2006;2:209–15. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17502920
Ohashi K, Burkart V, Flohé S, Kolb H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol. 2000;164:558–61. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10623794
Vabulas RM, Ahmad-Nejad P, da Costa C, Miethke T, Kirschning CJ, Häcker H, et al. Endocytosed HSP60s use toll-like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin-1 receptor signaling pathway in innate immune cells. J Biol Chem. 2001;276:31332–9. Available from: http://www.jbc.org/lookup/doi/10.1074/jbc.M103217200
Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, et al. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem. 2002;277:15028–34. Available from: http://www.jbc.org/lookup/doi/10.1074/jbc.M200497200
Delneste Y, Magistrelli G, Gauchat J, Haeuw J, Aubry J, Nakamura K, et al. Involvement of LOX-1 in dendritic cell-mediated antigen cross-presentation. Immunity. 2002;17:353–62. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12354387
Delneste Y. Scavenger receptors and heat-shock protein-mediated antigen cross-presentation. Biochem Soc Trans. 2004;32:633–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15270694
Nakamura T, Hinagata J, Tanaka T, Imanishi T, Wada Y, Kodama T, et al. HSP90, HSP70, and GAPDH directly interact with the cytoplasmic domain of macrophage scavenger receptors. Biochem Biophys Res Commun. 2002;290:858–64. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0006291X01962710
Becker T, Hartl F-U, Wieland F. CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes. J Cell Biol. 2002;158:1277–85. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12356871
Binder RJ, Srivastava PK. Essential role of CD91 in re-presentation of gp96-chaperoned peptides. Proc Natl Acad Sci U S A. 2004;101:6128–33. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.0308180101
Stebbing J, Savage P, Patterson S, Gazzard B. All for CD91 and CD91 for all. J Antimicrob Chemother. 2003;53:1–3. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14657092
Thériault JR, Mambula SS, Sawamura T, Stevenson MA, Calderwood SK. Extracellular HSP70 binding to surface receptors present on antigen presenting cells and endothelial/epithelial cells. FEBS Lett. 2005;579:1951–60. Available from: http://doi.wiley.com/10.1016/j.febslet.2005.02.046
Calderwood SK, Mambula SS, Gray PJ, Theriault JR. Extracellular heat shock proteins in cell signaling. FEBS Lett. 2007;581:3689–94. Available from: http://doi.wiley.com/10.1016/j.febslet.2007.04.044
Berwin B, Hart JP, Rice S, Gass C, Pizzo SV, Post SR, et al. Scavenger receptor-A mediates gp96/GRP94 and calreticulin internalization by antigen-presenting cells. EMBO J. 2003;22:6127–36. Available from: http://emboj.embopress.org/cgi/doi/10.1093/emboj/cdg572
Morimoto RI, Santoro MG. Stress-inducible responses and heat shock proteins: new pharmacologic targets for cytoprotection. Nat Biotechnol. 1998;16:833–8. Available from: http://www.nature.com/doifinder/10.1038/nbt0998-833
Santoro MG. Heat shock factors and the control of the stress response. Biochem Pharmacol. 2000;59:55–63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10605935
Salari S, Seibert T, Chen Y-X, Hu T, Shi C, Zhao X, et al. Extracellular HSP27 acts as a signaling molecule to activate NF-κB in macrophages. Cell Stress Chaperones. 2013;18:53–63. Available from: http://link.springer.com/10.1007/s12192-012-0356-0
Fernández-Fernández MR, Gragera M, Ochoa-Ibarrola L, Quintana-Gallardo L, Valpuesta JM. Hsp70 – a master regulator in protein degradation. FEBS Lett. 2017;591:2648–60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28696498
Calderwood SK, Murshid A, Gong J. Heat shock proteins: conditional mediators of inflammation in tumor immunity. Front Immunol. 2012;3:75. Available from: http://journal.frontiersin.org/article/10.3389/fimmu.2012.00075/abstract
van Eden W, Spiering R, Broere F, van der Zee R. A case of mistaken identity: HSPs are no DAMPs but DAMPERs. Cell Stress Chaperones. 2012;17:281–92. Available from: http://link.springer.com/10.1007/s12192-011-0311-5
Koliński T, Marek-Trzonkowska N, Trzonkowski P, Siebert J. Heat shock proteins (HSPs) in the homeostasis of regulatory T cells (Tregs). Cent Eur J Immunol. 2016;3:317–23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27833451
Sedaghat F, Notopoulos A. S100 protein family and its application in clinical practice. Hippokratia. 2008;12:198–204. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19158963
Timmermans K, Kox M, Scheffer GJ, Pickkers P. Danger in the intesive care unit: DAMPs in critically ill patients. Shock. 2016;45:108–16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26513703
Foell D, Wittkowski H, Vogl T, Roth J. S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol. 2007;81:28–37. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16943388
Ellis EF, Willoughby KA, Sparks SA, Chen T. S100B protein is released from rat neonatal neurons, astrocytes, and microglia by in vitro trauma and anti-S100 increases trauma-induced delayed neuronal injury and negates the protective effect of exogenous S100B on neurons. J Neurochem. 2007;101:1463–70. Available from: http://doi.wiley.com/10.1111/j.1471-4159.2007.04515.x
Michetti F, Corvino V, Geloso MC, Lattanzi W, Bernardini C, Serpero L, et al. The S100B protein in biological fluids: more than a lifelong biomarker of brain distress. J Neurochem. 2012;120:644–59. Available from: http://doi.wiley.com/10.1111/j.1471-4159.2011.07612.x
Oesterle A, Hofmann Bowman MA. S100A12 and the S100/CalgranulinsSignificance. Arterioscler Thromb Vasc Biol. 2015;35:2496–507. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26515415
Jackson E, Little S, Franklin DS, Gaddy JA, Damo SM. Expression, purification, and antimicrobial activity of S100A12. J Vis Exp. 2017.; Available from: http://www.ncbi.nlm.nih.gov/pubmed/28570542
Donato R, Sorci G, Riuzzi F, Arcuri C, Bianchi R, Brozzi F, et al. S100B’s double life: intracellular regulator and extracellular signal. Biochim Biophys Acta. 2009;1793:1008–22. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0167488908004096
Ma L, Sun P, Zhang J-C, Zhang Q, Yao S-L. Proinflammatory effects of S100A8/A9 via TLR4 and RAGE signaling pathways in BV-2 microglial cells. Int J Mol Med. 2017;40:31–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28498464
Chen B, Miller AL, Rebelatto M, Brewah Y, Rowe DC, Clarke L, et al. S100A9 induced inflammatory responses are mediated by distinct damage associated molecular patterns (DAMP) receptors in vitro and in vivo. PLoS One. 2015;10:e0115828. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25706559
He Z, Riva M, Björk P, Swärd K, Mörgelin M, Leanderson T, et al. CD14 is a co-receptor for TLR4 in the S100A9-induced pro-inflammatory response in monocytes. PLoS One. 2016;11:e0156377. Available from: http://dx.plos.org/10.1371/journal.pone.0156377
Foell D, Wittkowski H, Kessel C, Lüken A, Weinhage T, Varga G, et al. Proinflammatory S100A12 can activate human monocytes via toll-like receptor 4. Am J Respir Crit Care Med. 2013;187:1324–34. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23611140
Bagheri V. S100A12: friend or foe in pulmonary tuberculosis? Cytokine. 2017;92:80–2. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28110121
Jensen JL, Indurthi VSK, Neau DB, Vetter SW, Colbert CL. Structural insights into the binding of the human receptor for advanced glycation end products (RAGE) by S100B, as revealed by an S100B–RAGE-derived peptide complex. Acta Crystallogr Sect D Biol Crystallogr. 2015;71:1176–83. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25945582
Donato R, Cannon BR, Sorci G, Riuzzi F, Hsu K, Weber DJ, et al. Functions of S100 proteins. Curr Mol Med. 2013;13:24–57. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22834835
Gross SR, Sin CGT, Barraclough R, Rudland PS. Joining S100 proteins and migration: for better or for worse, in sickness and in health. Cell Mol Life Sci. 2014;71:1551–79. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23811936
Lande R, Ganguly D, Facchinetti V, Frasca L, Conrad C, Gregorio J, et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med. 2011;3:73ra19. Available from: http://wwww.stm.sciencemag.org/cgi/doi/10.1126/scitranslmed.3001180
Nakahira K, Hisata S, Choi AMK. The roles of mitochondrial damage-associated molecular patterns in diseases. Antioxid Redox Signal. 2015;23:1329–50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26067258
Pazmandi K, Agod Z, Kumar BV, Szabo A, Fekete T, Sogor V, et al. Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells. Free Radic Biol Med. 2014;77:281–90. Available from: http://linkinghub.elsevier.com/retrieve/pii/S089158491400447X
Roers A, Hiller B, Hornung V. Recognition of endogenous nucleic acids by the innate immune system. Immunity. 2016;44:739–54. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27096317
Ablasser A, Hertrich C, Waßermann R, Hornung V. Nucleic acid driven sterile inflammation. Clin Immunol. 2013;147:207–15. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1521661613000041
Miyake K, Shibata T, Ohto U, Shimizu T. Emerging roles of the processing of nucleic acids and Toll-like receptors in innate immune responses to nucleic acids. J Leukoc Biol. 2017;101:135–42. Available from: http://www.jleukbio.org/lookup/doi/10.1189/jlb.4MR0316-108R
Hartmann G. Nucleic acid immunity. Adv Immunol. 2017;133:121–69. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28215278
Zhang Z, Ohto U, Shimizu T. Toward a structural understanding of nucleic acid-sensing Toll-like receptors in the innate immune system. FEBS Lett. 2017;591(20):3167–81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28686285
Land WG. Innate alloimmunity Part 1. Innate immunity and host defense. Baskent University, Ankara; Pabst Science Publishers, Lengerich; 2011. Available from: ISBN 978-3-389967-737-9
Isaacs A, Cox RA, Rotem Z. Foreign nucleic acids as the stimulus to make interferon. Lancet (London). 1963;2:113–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/13956740
Itagaki K, Kaczmarek E, Lee YT, Tang IT, Isal B, Adibnia Y, et al. Mitochondrial DNA released by trauma induces neutrophil extracellular traps. PLoS One. 2015;e0120549:10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25774524
Magna M, Pisetsky DS. The alarmin properties of DNA and DNA-associated nuclear proteins. Clin Ther. 2016;38:1029–41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27021604
Huang H, Evankovich J, Yan W, Nace G, Zhang L, Ross M, et al. Endogenous histones function as alarmins in sterile inflammatory liver injury through Toll-like receptor 9 in mice. Hepatology. 2011;54:999–1008. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21721026
Xu J, Zhang X, Monestier M, Esmon NL, Esmon CT. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J Immunol. 2011;187:2626–31. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21784973
Allam R, Kumar SVR, Darisipudi MN, Anders H-J. Extracellular histones in tissue injury and inflammation. J Mol Med (Berl). 2014;92:465–72. Available from: http://link.springer.com/10.1007/s00109-014-1148-z
Marsman G, Zeerleder S, Luken BM. Extracellular histones, cell-free DNA, or nucleosomes: differences in immunostimulation. Cell Death Dis. 2016;7:e2518. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27929534
Santos TG, Martins V, Hajj G. Unconventional secretion of heat shock proteins in cancer. Int J Mol Sci. 2017;18:946. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28468249
Silk E, Zhao H, Weng H, Ma D. The role of extracellular histone in organ injury. Cell Death Dis. 2017;8:e2812. Available from: http://www.nature.com/doifinder/10.1038/cddis.2017.52
Allam R, Scherbaum CR, Darisipudi MN, Mulay SR, Hagele H, Lichtnekert J, et al. Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4. J Am Soc Nephrol. 2012;23:1375–88. Available from: http://www.jasn.org/cgi/doi/10.1681/ASN.2011111077
Decker P, Singh-Jasuja H, Haager S, Kötter I, Rammensee H-G. Nucleosome, the main autoantigen in systemic lupus erythematosus, induces direct dendritic cell activation via a MyD88-independent pathway: consequences on inflammation. J Immunol. 2005;174:3326–34. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15749864
Linkermann A, Stockwell BR, Krautwald S, Anders H-J. Regulated cell death and inflammation: an auto-amplification loop causes organ failure. Nat Rev Immunol. 2014;14:759–67. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25324125
Xu J, Zhang X, Pelayo R, Monestier M, Ammollo CT, Semeraro F, et al. Extracellular histones are major mediators of death in sepsis. Nat Med. 2009;15:1318–21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19855397
Kawai C, Kotani H, Miyao M, Ishida T, Jemail L, Abiru H, et al. Circulating extracellular histones are clinically relevant mediators of multiple organ injury. Am J Pathol. 2016;186:829–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26878212
Roussel L, Erard M, Cayrol C, Girard J-P. Molecular mimicry between IL-33 and KSHV for attachment to chromatin through the H2A-H2B acidic pocket. EMBO Rep. 2008;9:1006–12. Available from: http://embor.embopress.org/cgi/doi/10.1038/embor.2008.145
Moussion C, Ortega N, Girard J-P. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel “alarmin”? PLoS One. 2008;3:e3331. Available from: http://dx.plos.org/10.1371/journal.pone.0003331
Cayrol C, Girard J-P. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc Natl Acad Sci U S A. 2009;106:9021–6. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.0812690106
Lüthi AU, Cullen SP, McNeela EA, Duriez PJ, Afonina IS, Sheridan C, et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity. 2009;31:84–98. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1074761309002696
Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10:826–37. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21088683
Martin SJ. Cell death and inflammation: the case for IL-1 family cytokines as the canonical DAMPs of the immune system. FEBS J. 2016;283:2599–615. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27273805
Cayrol C, Girard J-P. IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy. Curr Opin Immunol. 2014;31:31–7. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0952791514001101
Bertheloot D, Latz E. HMGB1, IL-1α, IL-33 and S100 proteins: dual-function alarmins. Cell Mol Immunol. 2017;14:43–64. Available from: http://www.nature.com/doifinder/10.1038/cmi.2016.34
Lefrançais E, Roga S, Gautier V, Gonzalez-de-Peredo A, Monsarrat B, Girard J-P, et al. IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G. Proc Natl Acad Sci U S A. 2012;109:1673–8. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.1115884109
Kim B, Lee Y, Kim E, Kwak A, Ryoo S, Bae SH, et al. The interleukin-1α precursor is biologically active and is likely a key alarmin in the IL-1 family of cytokines. Front Immunol. 2013;4:391. Available from: http://journal.frontiersin.org/article/10.3389/fimmu.2013.00391/abstract
Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519–50. Available from: http://www.annualreviews.org/doi/10.1146/annurev.immunol.021908.132612
Eigenbrod T, Park J-H, Harder J, Iwakura Y, Núñez G. Cutting edge: critical role for mesothelial cells in necrosis-induced inflammation through the recognition of IL-1 alpha released from dying cells. J Immunol. 2008;181:8194–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19050234
Liu Y, Kimura K, Orita T, Sonoda K-H. Necrosis-induced sterile inflammation mediated by interleukin-1α in retinal pigment epithelial cells. PLoS One. 2015;e0144460:10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26641100
Fukuda K, Ishida W, Miura Y, Kishimoto T, Fukushima A. Cytokine expression and barrier disruption in human corneal epithelial cells induced by alarmin released from necrotic cells. Jpn J Ophthalmol. 2017;61:415–22. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28725984
Mosley B, Urdal DL, Prickett KS, Larsen A, Cosman D, Conlon PJ, et al. The interleukin-1 receptor binds the human interleukin-1 alpha precursor but not the interleukin-1 beta precursor. J Biol Chem. 1987;262:2941–4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2950091
Carp H. Mitochondrial N-formylmethionyl proteins as chemoattractants for neutrophils. J Exp Med. 1982;155:264–75. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6274994
Le Y, Murphy PM, Wang JM. Formyl-peptide receptors revisited. Trends Immunol. 2002;23:541–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12401407
Wenceslau CF, McCarthy CG, Szasz T, Goulopoulou S, Webb RC. Mitochondrial N-formyl peptides induce cardiovascular collapse and sepsis-like syndrome. Am J Physiol Heart Circ Physiol. 2015;308:H768–77. Available from: http://ajpheart.physiology.org/lookup/doi/10.1152/ajpheart.00779.2014
Wenceslau CF, McCarthy CG, Szasz T, Spitler K, Goulopoulou S, Webb RC, et al. Mitochondrial damage-associated molecular patterns and vascular function. Eur Heart J. 2014;35:1172–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24569027
Marutani T, Hattori T, Tsutsumi K, Koike Y, Harada A, Noguchi K, et al. Mitochondrial protein-derived cryptides: are endogenous N-formylated peptides including mitocryptide-2 components of mitochondrial damage-associated molecular patterns? Biopolymers. 2016;106:580–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26600263
Dorward DA, Lucas CD, Chapman GB, Haslett C, Dhaliwal K, Rossi AG. The role of formylated peptides and formyl peptide receptor 1 in governing neutrophil function during acute inflammation. Am J Pathol. 2015;185:1172–84. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25791526
Eleftheriadis T, Pissas G, Liakopoulos V, Stefanidis I. Cytochrome c as a potentially clinical useful marker of mitochondrial and cellular damage. Front Immunol. 2016;7:279. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27489552
Wenceslau CF, Szasz T, McCarthy CG, Baban B, NeSmith E, Webb RC. Mitochondrial N-formyl peptides cause airway contraction and lung neutrophil infiltration via formyl peptide receptor activation. Pulm Pharmacol Ther. 2016;37:49–56. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26923940
He H-Q, Ye R. The formyl peptide receptors: diversity of ligands and mechanism for recognition. Molecules. 2017;22:455. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28335409
Pullerits R, Bokarewa M, Jonsson I-M, Verdrengh M, Tarkowski A. Extracellular cytochrome c, a mitochondrial apoptosis-related protein, induces arthritis. Rheumatology (Oxford). 2005;44:32–9. Available from: https://academic.oup.com/rheumatology/article-lookup/doi/10.1093/rheumatology/keh406
Gouveia A, Bajwa E, Klegeris A. Extracellular cytochrome c as an intercellular signaling molecule regulating microglial functions. Biochim Biophys Acta Gen Subj. 2017;1861:2274–81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28652078
Ahrens S, Zelenay S, Sancho D, Hanč P, Kjær S, Feest C, et al. F-actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity. 2012;36:635–45. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22483800
Srinivasan N, Gordon O, Ahrens S, Franz A, Deddouche S, Chakravarty P, et al. Actin is an evolutionarily-conserved damage-associated molecular pattern that signals tissue injury in Drosophila melanogaster. Ltd: Elife eLife Sciences Publications; 2016. p. 5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27871362
Reis E, Sousa C. Sensing infection and tissue damage. EMBO Mol Med. 2017;9:285–8. Available from: http://embomolmed.embopress.org/lookup/doi/10.15252/emmm.201607227
Sancho D, Joffre OP, Keller AM, Rogers NC, Martínez D, Hernanz-Falcón P, et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature. 2009;458:899–903. Available from: http://www.nature.com/doifinder/10.1038/nature07750
Figueiredo RT, Fernandez PL, Mourao-Sa DS, Porto BN, Dutra FF, Alves LS, et al. Characterization of heme as activator of Toll-like receptor 4. J Biol Chem. 2007;282:20221–9. Available from: http://www.jbc.org/lookup/doi/10.1074/jbc.M610737200
Mendonça R, Silveira AAA, Conran N. Red cell DAMPs and inflammation. Inflamm Res. 2016;65:665–78. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27251171
Land WG. Transfusion-related acute lung injury: the work of DAMPs. Transfus Med Hemother. 2013;40:3–13. Available from: http://www.karger.com/doi/10.1159/000345688
Jeney V, Balla J, Yachie A, Varga Z, Vercellotti GM, Eaton JW, et al. Pro-oxidant and cytotoxic effects of circulating heme. Blood. 2002;100:879–87. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12130498
Porto BN, Alves LS, Fernández PL, Dutra TP, Figueiredo RT, Graça-Souza AV, et al. Heme induces neutrophil migration and reactive oxygen species generation through signaling pathways characteristic of chemotactic receptors. J Biol Chem. 2007;282:24430–6. Available from: http://www.jbc.org/lookup/doi/10.1074/jbc.M703570200
Dutra FF, Bozza MT. Heme on innate immunity and inflammation. Front Pharmacol. 2014;5:115. Available from: http://journal.frontiersin.org/article/10.3389/fphar.2014.00115/abstract
Dutra FF, Alves LS, Rodrigues D, Fernandez PL, de Oliveira RB, Golenbock DT, et al. Hemolysis-induced lethality involves inflammasome activation by heme. Proc Natl Acad Sci. 2014;111:E4110–8. Available from: http://www.pnas.org/lookup/doi/10.1073/pnas.1405023111
Belcher JD, Chen C, Nguyen J, Milbauer L, Abdulla F, Alayash AI, et al. Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease. Blood. 2014;123:377–90. Available from: http://www.bloodjournal.org/cgi/doi/10.1182/blood-2013-04-495887
Frimat M, Tabarin F, Dimitrov JD, Poitou C, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, et al. Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome. Blood. 2013;122:282–92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23692858
Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006;440:228–32. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16407890
Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16407889
Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008;9:847–56. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18604214
Elliott EI, Sutterwala FS. Initiation and perpetuation of NLRP3 inflammasome activation and assembly. Immunol Rev. 2015;265:35–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25879282
Man SM, Kanneganti T-D. Regulation of inflammasome activation. Immunol Rev. 2015;265:6–21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25879280
Jo E-K, Kim JK, Shin D-M, Sasakawa C. Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol. 2016;13:148–59. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26549800
Miao EA, Rajan JV, Aderem A. Caspase-1-induced pyroptotic cell death. Immunol Rev. 2011;243:206–14. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21884178
Gordon JL. Extracellular ATP: effects, sources and fate. Biochem J. 1986;233:309–19. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3006665
Khakh BS, Burnstock G. The double life of ATP. Sci Am. 2009;301:84–90, 92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20058644
Iyer SS, Pulskens WP, Sadler JJ, Butter LM, Teske GJ, Ulland TK, et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc Natl Acad Sci U S A. 2009;106:20388–93. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19918053
Eltzschig HK, Sitkovsky MV, Robson SC. Purinergic signaling during inflammation. N. Engl. J. N Engl J Med. 2012;367:2322–33. Available from: http://www.nejm.org/doi/abs/10.1056/NEJMra1205750
Idzko M, Ferrari D, Eltzschig HK. Nucleotide signalling during inflammation. Nature. 2014;509:310–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24828189
Yaron JR, Gangaraju S, Rao MY, Kong X, Zhang L, Su F, et al. K(+) regulates Ca(2+) to drive inflammasome signaling: dynamic visualization of ion flux in live cells. Cell Death Dis. 2015;e1954:6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26512962
Di Virgilio F, Vuerich M. Purinergic signaling in the immune system. Auton Neurosci. 2015;191:117–23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25979766
Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A, Walk SF, et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature. 2009;461:282–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19741708
Rock KL, Kataoka H, Lai J-J. Uric acid as a danger signal in gout and its comorbidities. Nat Rev Rheumatol. 2013;9:13–23. Available from: http://www.nature.com/doifinder/10.1038/nrrheum.2012.143
Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature. 2003;425:516–21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14520412
Kono H, Chen C-J, Ontiveros F, Rock KL. Uric acid promotes an acute inflammatory response to sterile cell death in mice. J Clin Invest. 2010;120:1939–49. Available from: http://www.jci.org/articles/view/40124
Latz E. The inflammasomes: mechanisms of activation and function. Curr Opin Immunol. 2010;22:28–33. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0952791509002271
Yang M, Hearnden CHA, Oleszycka E, Lavelle EC. NLRP3 inflammasome activation and cytotoxicity induced by particulate adjuvants. Methods Mol Biol. 2013;1040:41–63. Available from: http://link.springer.com/10.1007/978-1-62703-523-1_5
Bainton DF, Takemura R, Stenberg PE, Werb Z. Rapid fragmentation and reorganization of Golgi membranes during frustrated phagocytosis of immobile immune complexes by macrophages. Am J Pathol. 1989;134:15–26. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2913823
Ea H-K, So A, Liote F, Busso N. Basic calcium phosphate crystals induce NLRP3 inflammasome activation: the in vitro and in vivo face to face. Proc Natl Acad Sci. 2011;108:E1361. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22123977
Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science (80). 2008;320:674–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18403674
Goedeke L, Fernández-Hernando C. Regulation of cholesterol homeostasis. Cell Mol Life Sci. 2012;69:915–30. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22009455
Pizzini A, Lunger L, Demetz E, Hilbe R, Weiss G, Ebenbichler C, et al. The role of omega-3 fatty acids in reverse cholesterol transport: a review. Nutrients. 2017;9:1099. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28984832
Tangirala RK, Jerome WG, Jones NL, Small DM, Johnson WJ, Glick JM, et al. Formation of cholesterol monohydrate crystals in macrophage-derived foam cells. J Lipid Res. 1994;35:93–104. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8138726
Lim RS, Suhalim JL, Miyazaki-Anzai S, Miyazaki M, Levi M, Potma EO, et al. Identification of cholesterol crystals in plaques of atherosclerotic mice using hyperspectral CARS imaging. J Lipid Res. 2011;52:2177–86. Available from: http://www.jlr.org/lookup/doi/10.1194/jlr.M018077
Libby P, Hansson GK. Inflammation and immunity in diseases of the arterial tree: players and layers. Circ Res. 2015;116:307–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25593275
Tall AR, Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nat Rev Immunol. 2015;15:104–16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25614320
Bennett MR, Sinha S, Owens GK. Vascular smooth muscle cells in atherosclerosis. Circ Res. 2016;118:692–702. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26892967
Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357–61. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20428172
Rajamäki K, Lappalainen J, Oörni K, Välimäki E, Matikainen S, Kovanen PT, et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One. 2010;e11765:5. Available from: http://dx.plos.org/10.1371/journal.pone.0011765
Christ A, Bekkering S, Latz E, Riksen NP. Long-term activation of the innate immune system in atherosclerosis. Semin Immunol. 2016;28:384–93. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27113267
Ketelhuth DF, Hansson GK. Modulation of autoimmunity and atherosclerosis – common targets and promising translational approaches against disease. Circ J. 2015;79:924–33. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25766275
Alberti KGMM, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International. Circulation. 2009;120:1640–5. Available from: http://circ.ahajournals.org/cgi/doi/10.1161/CIRCULATIONAHA.109.192644
Kaur J. A comprehensive review on metabolic syndrome. Cardiol Res Pract. 2014;2014:943162. Available from: http://www.hindawi.com/journals/crp/2014/943162/
De Nardo D, Latz E. NLRP3 inflammasomes link inflammation and metabolic disease. Trends Immunol. 2011;32:373–9. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1471490611000822
Vandanmagsar B, Youm Y-H, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011;17:179–88. Available from: http://www.nature.com/doifinder/10.1038/nm.2279
Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT-H, et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol. 2011;12:408–15. Available from: http://www.nature.com/doifinder/10.1038/ni.2022
Weber K, Schilling JD. Lysosomes integrate metabolic-inflammatory cross-talk in primary macrophage inflammasome activation. J Biol Chem. 2014;289:9158–71. Available from: http://www.jbc.org/lookup/doi/10.1074/jbc.M113.531202
Szpigel A, Hainault I, Carlier A, Venteclef N, Batto A-F, Hajduch E, et al. Lipid environment induces ER stress, TXNIP expression and inflammation in immune cells of individuals with type 2 diabetes. Diabetologia. 2018;61(2):399–412. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28988346
Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8:595–608. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27025652
Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat Immunol. 2008;9:857–65. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18604209
Takada LT. Innate immunity and inflammation in Alzheimer’s disease pathogenesis. Arq Neuropsiquiatr. 2017;75:607–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28977138
Heneka MT. Inflammasome activation and innate immunity in Alzheimer’s disease. Brain Pathol. 2017;27:220–2. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28019679
Codolo G, Plotegher N, Pozzobon T, Brucale M, Tessari I, Bubacco L, et al. Triggering of inflammasome by aggregated α–synuclein, an inflammatory response in synucleinopathies. PLoS One. 2013;e55375:8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23383169
Gustot A, Gallea JI, Sarroukh R, Celej MS, Ruysschaert J-M, Raussens V. Amyloid fibrils are the molecular trigger of inflammation in Parkinson’s disease. Biochem J. 2015;471:323–33. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26272943
Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat Immunol. 2010;11:897–904. Available from: http://www.nature.com/doifinder/10.1038/ni.1935
Meier DT, Morcos M, Samarasekera T, Zraika S, Hull RL, Kahn SE. Islet amyloid formation is an important determinant for inducing islet inflammation in high-fat-fed human IAPP transgenic mice. Diabetologia. 2014;57:1884–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24965964
Westwell-Roper C, Denroche HC, Ehses JA, Verchere CB. Differential activation of innate immune pathways by distinct islet amyloid polypeptide (IAPP) aggregates. J Biol Chem. 2016;291:8908–17. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26786104
Lee H-M, Kim J-J, Kim HJ, Shong M, Ku BJ, Jo E-K. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes. 2013;62:194–204. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23086037
Prabhudas M, Bowdish D, Drickamer K, Febbraio M, Herz J, Kobzik L, et al. Standardizing scavenger receptor nomenclature. J Immunol. 2014;192:1997–2006. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24563502
Zani IA, Stephen SL, Mughal NA, Russell D, Homer-Vanniasinkam S, Wheatcroft SB, et al. Scavenger receptor structure and function in health and disease. Cell. 2015;4:178–201. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26010753
Lillis AP, Van Duyn LB, Murphy-Ullrich JE, Strickland DK. LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol Rev. 2008;88:887–918. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18626063
Cappelletti M, Presicce P, Calcaterra F, Mavilio D, Della Bella S. Bright expression of CD91 identifies highly activated human dendritic cells that can be expanded by defensins. Immunology. 2015;144:661–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25351513
Raghavan M, Wijeyesakere SJ, Peters LR, Del Cid N. Calreticulin in the immune system: ins and outs. Trends Immunol. 2013;34:13–21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22959412
Gold L, Williams D, Groenendyk J, Michalak M, Eggleton P. Unfolding the complexities of ER chaperones in health and disease: report on the 11th international calreticulin workshop. Cell Stress Chaperones. 2015;20:875–83. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26395641
Michalak M, Corbett EF, Mesaeli N, Nakamura K, Opas M. Calreticulin: one protein, one gene, many functions. Biochem J. 1999;344(Pt 2):281–92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10567207
Gao B, Adhikari R, Howarth M, Nakamura K, Gold MC, Hill AB, et al. Assembly and antigen-presenting function of MHC class I molecules in cells lacking the ER chaperone calreticulin. Immunity. 2002;16:99–109. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11825569
Panaretakis T, Kepp O, Brockmeier U, Tesniere A, Bjorklund A-C, Chapman DC, et al. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J. 2009;28:578–90. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19165151
Gardai SJ, McPhillips KA, Frasch SC, Janssen WJ, Starefeldt A, Murphy-Ullrich JE, et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell. 2005;123:321–34. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16239148
Martins I, Kepp O, Galluzzi L, Senovilla L, Schlemmer F, Adjemian S, et al. Surface-exposed calreticulin in the interaction between dying cells and phagocytes. Ann N Y Acad Sci. 2010;1209:77–82. Available from: http://doi.wiley.com/10.1111/j.1749-6632.2010.05740.x
Arandjelovic S, Ravichandran KS. Phagocytosis of apoptotic cells in homeostasis. Nat Immunol. 2015;16:907–17. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26287597
Kepp O, Menger L, Vacchelli E, Locher C, Adjemian S, Yamazaki T, et al. Crosstalk between ER stress and immunogenic cell death. Cytokine Growth Factor Rev. 2013;24:311–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23787159
Pawaria S, Binder RJ. CD91-dependent programming of T-helper cell responses following heat shock protein immunization. Nat Commun. 2011;2:521. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22045000
Osman R, Tacnet-Delorme P, Kleman J-P, Millet A, Frachet P. Calreticulin release at an early stage of death modulates the clearance by macrophages of apoptotic cells. Front Immunol. 2017;8:1034. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28878781
Liu R, Gong J, Chen J, Li Q, Song C, Zhang J, et al. Calreticulin as a potential diagnostic biomarker for lung cancer. Cancer Immunol Immunother. 2012;61:855–64. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22083347
Duo C-C, Gong F-Y, He X-Y, Li Y-M, Wang J, Zhang J-P, et al. Soluble calreticulin induces tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 production by macrophages through mitogen-activated protein kinase (MAPK) and NFκB signaling pathways. Int J Mol Sci. 2014;15:2916–28. Available from: http://www.mdpi.com/1422-0067/15/2/2916/
Feng H, Zeng Y, Whitesell L, Katsanis E. Stressed apoptotic tumor cells express heat shock proteins and elicit tumor-specific immunity. Blood. 2001;97:3505–12. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11369644
Adkins I, Sadilkova L, Hradilova N, Tomala J, Kovar M, Spisek R. Severe, but not mild heat-shock treatment induces immunogenic cell death in cancer cells. Oncoimmunology. 2017;6:e1311433. Available from: https://www.tandfonline.com/doi/full/10.1080/2162402X.2017.1311433
Zhang Y, Zheng L. Tumor immunotherapy based on tumor-derived heat shock proteins (Review). Oncol Lett. 2013;6:1543–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24260044
Xu Y, Wang Y, Zhao B, Zhang X, Fan H, Li X, et al. Activation of anti-HBV immune activity by DNA vaccine via electroporation using heat shock proteins as adjuvant. Sheng Wu Gong Cheng Xue Bao. 2013;29:1765–75. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24660624
Wang X-P, Wang Q-X, Lin H-P, Xu B, Zhao Q, Chen K. Recombinant heat shock protein 70 functional peptide and alpha-fetoprotein epitope peptide vaccine elicits specific anti-tumor immunity. Oncotarget. 2015;7:71274–84. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27713135
Carapito R.. Personal communication.
Carapito R, Bahram S. Genetics, genomics, and evolutionary biology of NKG2D ligands. Immunol Rev. 2015;267:88–116. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26284473
Lanier LL. NKG2D receptor and its ligands in host defense. Cancer Immunol Res. 2015;3:575–82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26041808
Moretta L, Montaldo E, Vacca P, Del Zotto G, Moretta F, Merli P, et al. Human natural killer cells: origin, receptors, function, and clinical applications. Int Arch Allergy Immunol. 2014;164:253–64. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25323661
Bahram S, Bresnahan M, Geraghty DE, Spies T. A second lineage of mammalian major histocompatibility complex class I genes. Proc Natl Acad Sci U S A. 1994;91:6259–63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8022771
Bahram S, Mizuki N, Inoko H, Spies T. Nucleotide sequence of the human MHC class I MICA gene. Immunogenetics. 1996;44:80–1. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8613147
Radosavljevic M, Cuillerier B, Wilson MJ, Clément O, Wicker S, Gilfillan S, et al. A cluster of ten novel MHC class I related genes on human chromosome 6q24.2-q25.3. Genomics. 2002;79:114–23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11827464
Iannello A, Raulet DH. Immune surveillance of unhealthy cells by natural killer cells. Cold Spring Harb Symp Quant Biol. 2013;78:249–57. Available from: http://symposium.cshlp.org/cgi/doi/10.1101/sqb.2013.78.020255
Raulet DH, Gasser S, Gowen BG, Deng W, Jung H. Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol. 2013;31:413–41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23298206
Carapito R, Jung N, Kwemou M, Untrau M, Michel S, Pichot A, et al. Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD. Blood. 2016;128:1979–86. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27549307
Tonnus W, Linkermann A. “Death is my Heir”—ferroptosis connects cancer pharmacogenomics and ischemia-reperfusion injury. Cell Chem Biol. 2016;23:202–3. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26971867
Tonnus W, Linkermann A. The in vivo evidence for regulated necrosis. Immunol Rev. 2017;277:128–49. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28462528
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Land, W.G. (2018). Endogenous DAMPs, Category I: Constitutively Expressed, Native Molecules (Cat. I DAMPs). In: Damage-Associated Molecular Patterns in Human Diseases. Springer, Cham. https://doi.org/10.1007/978-3-319-78655-1_12
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