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Signal Transduction Changes in Human Neutrophils with Age

  • Carl FortinEmail author
  • Tamas Fulop
  • Anis Larbi
  • Gilles Dupuis
Living reference work entry

Abstract

The role of innate immune cells as first line of defense against pathogens and foreign invasion has been widely recognized. Among the innate immune cells, neutrophils represent the most potent phagocytic cell and possess an elaborate arsenal capable of efficiently neutralizing pathogens; in addition, neutrophils modulate adaptive immunity by secreting cytokines. Over the years, it has become clear that human aging negatively affects neutrophils’ responses. A common alteration underlying these functional changes in aging is the decrease of phosphorylated forms of signaling molecules after receptor engagement. The consequences of aging on human neutrophils may impair the activation of immune responses and contribute to poorer vaccine responses and greater morbidity and mortality from infectious diseases in older adults. This chapter describes our current knowledge of the age-related alterations in receptors for the Nformyl-met-leu-phe (fMLP) peptide, for the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), and for Toll-like receptors (TLR) and triggering receptor expressed on myeloid cells-1 (TREM-1).

Keywords

Aging Human neutrophils Signal transduction N-formyl-met-leu-phe peptide receptor GM-CSF receptor TREM-1 receptor Lipid rafts 

Introduction

Human neutrophils, also known as polymorphonuclear leukocytes, are short-lived cells that play important roles in both host defense and acute inflammation and initiate the chronic low-grade inflammation called inflamm-aging (Monti et al. 2016). Intrinsic threats or pathogens will induce inflammatory responses in resident immune and epithelial cells, and this will initiate a cascade of reactions causing neutrophils to adhere to endothelial cells, extravasate from the blood vessels, migrate toward the inflamed areas by following a path of chemokines, and, if necessary, perform such functions as phagocytosis, free radical production, and the release of immune modulators. These functions are elicited through the engagement of receptors such as the formyl methionyl leucine phenyl (fMLP) receptor (FPR1), the granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR), and interleukin-8 (IL-8) receptors (Futosi et al. 2013). Other important receptors playing essential role in neutrophil functions are Fcγ receptors (Futosi et al. 2013). Particularly, it has been shown that FcγRIIIb cross-linking induced NET formation similar to PMA stimulation in human neutrophils (Alemán et al. 2016). NET formation was dependent on NADPH oxidase, PKC, and ERK activation. In addition to these well-known receptors, new activating receptors were recently found for neutrophils. For example, the family of pattern recognition receptors (PRRs) include at least ten Toll-like receptors (TLRs), which recognize conserved molecular structures found in prokaryotes and fungi (Medzhitov 2001; Krishnan et al. 2007). Another recent addition is the triggering receptor expressed on myeloid cells-1 (TREM-1). TREM-1 is a member of the immunoglobulin (Ig) superfamily of receptors and is upregulated at the surface of the neutrophils and monocytes during infection and in LPS-induced sepsis in mice (Bouchon et al. 2000; Bleharski et al. 2003; Gibot 2006).

Over the past few years, it has become clear that the neutrophils’ functions are changed in aging. As mentioned neutrophils are short-lived cells, so the debate is still ongoing whether the changes observed are already at the hematopoietic stem cell (HSC) level or are occurring through differentiation or by age-dependent extracellular factors. No direct experimental evidence suggests that the changes occur already at the HSC level. Data suggest that the dysfunctions as will be described in this chapter are mostly determined after their differentiation (Montgomery and Shaw 2015). Indeed, this was described for chemotaxis, phagocytosis, and intracellular killing and neutrophil extracellular trap (NET) formation, among others (Shaw et al. 2013; Hazeldine et al. 2014; Montgomery and Shaw 2015; and this handbook). These altered neutrophil functions may be clinically relevant as they play an important role in the inability of older individuals to mount an effective and timely orchestrated response to bacterial pathogens and are likely to impair the resolution of pulmonary inflammation. Thus, not only the eradication of the pathogens is altered, but the time to induce a chronic inflammatory process is increased (Miller and Linge 2017). Furthermore, as neutrophils have been shown to be able to modulate and even regulate other players of the host immune response such as NK cells (Valayer et al. 2017), dendritic cells (DCs) (Odobasic et al. 2016), and various T cells (Kalyan and Kabelitz 2014), we can only hypothesize that these functional changes with aging will have deleterious effects on the whole immune response (Fortin et al. 2008). Alterations in signaling pathways elicited by these activating receptors are probably linked to the changed capabilities of neutrophils with age, leading to a marked dysfunctional state. Although we recognize the essential role of Fcγ receptor in these neutrophil functions, the data in aging are scarce, so we will not discuss them in details (Fülöp et al. 1985). This chapter will hence describe our current knowledge of the age-related alterations in signal transduction of FPR1, GM-CSFR, TLR, and TREM-1 in human neutrophils.

N-Formyl-Met-Leu-Phe Peptide Receptor

In human neutrophils, formylated peptides, like the Nformyl-met-leu-phe (fMLP) peptide, are engaged to formyl peptide receptor 1 (FPR1) and trigger many neutrophil responses such as chemotaxis, upregulation of surface receptors, release of proteolytic enzymes from granules, and production of free radicals (Fulop et al. 2004; Fu et al. 2006). The FPR1 receptor belongs to the seven transmembrane G protein-coupled receptor (GPCR) family, and, because the Bordetella pertussis toxin largely inhibits neutrophils’ responses, it is thought that its signal transduction is dependent on a heterotrimeric G protein of the Gi type. Upon chemoattractant binding, GPCRs undergo a conformational change that enables them to interact with the Gi2 protein, thereby triggering both the exchange of GDP to GTP in the G protein α-subunit and the dissociation of the βγ-complex from the α-subunit (Gierschik et al. 1989). Following its dissociation from the α-subunit, the G protein βγ-subunits contribute to the activation of phospholipase Cβ2 (PLCβ2) (Camps et al. 1992) and of phosphoinositide 3-kinase-γ (PI3K-γ) (Stoyanov et al. 1995). PI3K-γ converts the membrane phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3), which is required both for the directed migration of neutrophils in a fMLP gradient and for the production of free radicals. Activation of PLCβ2, which induces the production of IP3, leads to an increase of cytosolic calcium and of diacylglycerol (DAG) concentrations, resulting in the translocation of protein kinase C (PKC) to the plasma membrane and in the phosphorylation of MAPK family members (Chang and Wang 1999, 2000). Neutrophils express the classical PKC isoforms (α, βI, and βII) and the novel PKC isoforms δ (Balasubramanian et al. 2002). Together, these two signaling pathways are thought to participate in different degrees to adherence, chemotaxis, and free radical production.

In aged neutrophils, the fMLP-induced production of free radicals was lower than in neutrophils of young donors (Lipschitz et al. 1988; Indelicato et al. 1990; Biasi et al. 1996). Moreover, the basal cytosolic calcium concentrations were altered with age; after fMLP activation, the flux of calcium to the cytosol was also reduced in neutrophils of elderly donors (Lipschitz et al. 1988). Conversely, the PMA-induced production of free radicals was not altered with age (Lipschitz et al. 1988; Indelicato et al. 1990; Hazeldine et al. 2014). These results strongly suggest that the signaling pathways elicited by fMLP are dysregulated in aging. As for other GPCRs, neutrophils from elderly blood donors were totally unresponsive compared to those of young blood donors when activated through CXCR1 by IL-8 (Dalboni et al. 2013), suggesting that the signaling pathways elicited by GFPCRs are altered in aging. Alternatively, the negative regulation of fMLP receptor could also be altered with age. For example, the inhibition of Lyn kinase was found to decrease the fMLP-induced migration of HL-60 cells (Nakata et al. 2006). As previous work reported that the Src homology domain-containing protein tyrosine phosphatase-1 (SHP-1) was overactivated in neutrophils of elderly donors and was physically associated with Lyn (Fortin et al. 2006), it is thus possible that dysregulation of phosphatase activity is an important factor in the decreased fMLP-induced functions in neutrophils of elderly donors. As for PKC, its activation by the Ras pathway leads to the activation of mitogen-activated protein kinase (MAPK) family members in neutrophils activated by fMLP (Zu et al. 1998). In aging, translocation of PKC to the membrane was normal in PMA-activated neutrophils, but the activation of PKC was reduced compared to young donors (Indelicato et al. 1990). Recently, the mitogen-activated protein 3 kinase, TGF-β-activated kinase 1 (TAK1), which is known to act upstream of MAPK kinases in other cell types, was found to be activated by fMLP in human neutrophils (Sylvain-Prevost et al. 2015). TAK1 provides a missing link between fMLPR and MAPK in neutrophils and is thus an interesting target for aging research. Finally, published data indicate that aging is associated with a decrease of extracellular signal-regulated kinase (ERK) and p38 MAPK tyrosine phosphorylation in fMLP-activated neutrophils (Larbi et al. 2006), suggesting that the decreased activity of these MAPKs partly explains the decreased effector functions of neutrophils in aging.

Granulocyte-Macrophage Colony-Stimulating Factor Receptor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a powerful modulator of granulopoiesis and enhances neutrophils’ responses to a second stimulation with fMLP or LPS. The receptor for GM-CSF, CD116, is a member of the superfamily of cytokine receptors (Geijsen et al. 2001). Its structure consists of a receptor-specific α-subunit and a β-subunit complex (βc) that is shared by IL-3 and IL-5 receptors (Geijsen et al. 2001). Although CD116 is not endowed with intrinsic protein kinase activity, its engagement by GM-CSF triggers the phosphorylation of its βc subunit on tyrosine residues by members of the Janus kinase family (JAK), which creates docking sites for multiple proteins containing the Src homology 2 (SH2) domains (Geijsen et al. 2001). GM-CSF has been shown to activate three distinct pathways in cells: (1) the JAK/STAT pathway, (2) the Ras-Raf-1-MEK-MAP kinase pathway, and (3) the PI3K intracellular signaling events (Sato et al. 1993; Watanabe et al. 1997). These pathways converge to induce the phosphorylation of cytoplasmic proteins on tyrosine residues, the expression of early response genes, and the proliferation of hematopoietic cells. In neutrophils, GM-CSF is an extremely potent apoptosis suppressor both in vivo and in vitro. And, the MAPK and PI3K pathways are required for this effect (Klein et al. 2000; Juss et al. 2012); indeed, they modulate the expression and stability of pro-apoptotic caspases and of Bcl-2 family members, which are key anti-apoptotic proteins (Kroemer et al. 1998) (Fig. 1).
Fig. 1

Signal transduction pathways of FMLP, GM-CSF, and LPS receptors. Alterations with age in receptor-elicited signaling pathways. In human neutrophils, fMLPR engagement leads to the activation of PI3K and PLCβ2; these, in turn, lead to the production of DAG and to increased cytosolic Ca2+ concentrations. These events activate the PKC family of kinases, which induce the activation of p38 MAPK and ERK1/2 through Ras. The ligand of GM-CSFR, for its part, induces the phosphorylation of residues in the ITAM of the common β-chain. These events will induce the recruitment of various signaling molecules to the GM-CSFR and will lead to the activation of p38 MAPK, ERK1/2, the JAK2-STAT1/3 pathway, and the PI3K-Akt/PKB pathway. Negative regulation of GM-CSFR is mediated by phosphatases, like SHP-1, that remove phospho-groups on ITAMs, or by the SOCS family of proteins, which binds JAK and other activating kinases, thus impeding the recruitment of signaling molecules on GM-CSFR. Upon engagement, TLR4 is recruited into the lipid rafts and with the adapter protein MyD88 leads to the activation of p38 MAPK, ERK1/2, and NF-κB through the IRAK/TRAFs and TAK1/TABs complexes. TLR4 also induces the activation of the PI3K-Akt/PKB pathway through unknown mechanisms. The downstream kinases and the transcription factors activated by these receptors mediate the functional responses of human neutrophils such as respiratory burst, chemotaxis, degranulation, and the production of cytokines and chemokines. The asterisks show the alterations with age in the signaling pathways of these receptors in human neutrophils. One can appreciate the work that remains to be done as the absence of asterisk indicates that potential alterations were not yet reported in aging. * Indicate experimentally proved changes with aging in human neutrophils. FMLP formyl methionyl leucine phenyl receptor, GM-CSF granulocyte-macrophage colony-stimulating factor receptor, LPS lipopolysaccharide receptor equivalent of Toll-like receptor 4

In elderly donors, GM-CSF is unable to rescue neutrophils from apoptosis (Fulop et al. 1997; Tortorella et al. 1998). Consequently, investigations were done to uncover whether the signaling transduction of the JAK/STAT pathway was altered in GM-CSF-activated neutrophils in aging. Neither short nor sustained phosphorylation of JAK2 could be found, and this inability of GM-CSF to induce JAK2 phosphorylation with age resulted in less phosphorylation of STAT3 and STAT5 (Fortin et al. 2007a). A strongly decreased phosphorylation of JAK2 in GM-CSF-activated neutrophils of elderly donors was also reported elsewhere (Tortorella et al. 2006). The density of the βc subunit was measured and found to be equal among age groups, as it was reported elsewhere for the expression of CD116 (Tortorella et al. 2006). Thus, the unchanged βc subunit expression insures an equal possibility of signaling in neutrophils of young and elderly donors. This is supported by the fact that the physical association between the GM-CSF receptor β-subunit and JAK2 was unchanged with age or with GM-CSF stimulation (Fortin et al. 2007a). Moreover, published results showed that AG490, a JAK2 inhibitor, could not influence the already decreased anti-apoptotic effect of GM-CSF. It is difficult to determine what the exact contribution of the JAK/STAT pathway in the anti-apoptotic effects of CD116 is, but these results indicate that it plays a proeminent role in the GM-CSF failure to rescue neutrophils of elderly donors from apoptosis. In addition, both the positive signaling events (kinases) and the negative signaling events (phosphatase) elicited by CD116 are altered in neutrophils with age. Indeed, the activity of SHP-1, a negative regulator of signal transduction, is dysregulated with age in GM-CSF-activated neutrophils (Fortin et al. 2006). This dysregulation hampered the phosphorylation of Src kinase Lyn and contributed to the impaired functions of neutrophils as its inhibition partly restored neutrophils’ functions in elderly donors (Fortin et al. 2006). Lastly, dysregulated activation with age of negative regulators like the suppressors of cytokine signaling (SOCS) proteins cannot be ruled out (Tortorella et al. 2007). Thus, neutrophils of elderly donors seem to be in a dominant negative status that induces a decreased sensitivity to GM-CSF.

These results suggest that if JAK2 phosphorylation is decreased, then other signaling pathways downstream of CD116 might also be altered. PI3K and the downstream serine/threonine kinase Akt/protein kinase B (Akt/PKB) have a central role in modulating neutrophil function in response to GM-CSF, but there are only inconclusive evidences to support that the phosphorylation of Akt is decreased with age (Tortorella et al. 2006). One possible explanation, however, was recently provided for this. Indeed, the MAP 3 K TAK1 was found to be activated in response to GM-CSF in human neutrophils, and its specific inhibition abrogated the phosphorylation of p38 MAPK and ERK1/ERK2, but not that of Akt/PKB (Sylvain-Prevost et al. 2015). This indicates that Akt/PKB is phosphorylated by a different upstream kinase than p38 MAPK and ERK1/ERK2 in neutrophils after CD116 engagement. Finally, three different kinases in the MAPK family are currently known: the extracellular-regulated kinase (ERK1/ERK2 or p42/44), the p38 MAPK, and the c-Jun terminal kinase (JNK). In aging, alterations in the GM-CSF-induced ERK1/ERK2 phosphorylation were reported, whereas conflicting results were found for the p38 MAPK (Tortorella et al. 2004; Larbi et al. 2005). Of note, no alterations with age were reported for TNF-α-induced ERK1/ERK2 phosphorylation (Tortorella et al. 2004). These suggest that some types of cytokine receptors may not have alterations in their signaling pathways with age.

As mentioned earlier, the signaling pathways elicited by GM-CSF converge to modulate the expression of pro- and anti-apoptotic proteins. As decreased phosphorylation of ERK1/ERK2 was reported with age, the expression of Bcl-2 family members was verified in neutrophils of elderly donors. It was found that the expression of Bcl-2-associated X protein (BAX) was strongly decreased in neutrophils of young donors after long-term stimulation with GM-CSF whereas the expression of B-cell lymphoma-extra large (Bcl-xL) was sustained (Larbi et al. 2005). With age, the expression of BAX was strong in neutrophils cultured for 18 h with GM-CSF, but the expression of Bcl-xL was strongly decreased compared to neutrophils of young donors (Larbi et al. 2005). These results showed that GM-CSF enabled the survival of neutrophils from young donors by decreasing the BAX/Bcl-xL ratio; when the ratio was calculated for neutrophils of elderly donors, however, the ratio was not decreased, but slightly increased (Larbi et al. 2005). Supporting this notion, GM-CSF has been shown to upregulate the expression of the anti-apoptotic Mcl-1 (Moulding et al. 1998; Epling-Burnette et al. 2001; Altznauer et al. 2004), whereas interferon (IFN)-α/(IFN)-γ had similar surviving effects by increasing the expression of cellular inhibitors of apoptosis protein 2 (cIAP2) proteins (Sakamoto et al. 2005). Moreover, the failure of GM-CSF to sustain STAT3 phosphorylation in neutrophils of elderly donors may promote apoptosis by failing to counteract the pro-apoptotic effects of activated STAT1, as it was reported in Mel80 cells (Shen et al. 2001).

Caspases (cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases) are a family of cysteine proteases that play essential roles in apoptosis. Caspase-3 is an effector caspase whose proteolytic activities eventually result in cell death. It was reported that GM-CSF was unable to downregulate caspase-3 activity in neutrophils of elderly donors (Larbi et al. 2005; Fortin et al. 2007a). Moreover, expression levels of both pro- and activated caspase-3 in neutrophils of elderly donors were increased (Larbi et al. 2005; Fortin et al. 2007a), indicating that the increase in caspases-3 activity likely reflects an increased abundance of this protein in neutrophils with age. Higher expression of pro-apoptotic proteins and caspases in cells with age appears to be a common phenomenon; this could, for example, explain the degeneration of tissues by increased levels of apoptosis in stem cells. Supporting this, it was reported that the concentration of active caspase-3 was about 35% higher in endothelial progenitor cells after staurosporine stimulation (Kushner et al. 2011). It is of note that bypassing CD116 by direct inhibition of caspase-3 was able to rescue neutrophils from apoptosis in both age groups (Fortin et al. 2007a). This further indicates that the GM-CSF’s inability to rescue neutrophils of elderly donors from apoptosis is linked to alterations in signal transduction between CD116 and caspase-3.

Toll-like Receptors

Toll-like receptors (TLRs) are germ-line encoded receptors able to detect conserved molecular patterns on microorganisms and pathogens. They are present on the cell surface and in intracellular endocytic compartments, and the engagement of TLR triggers powerful responses in innate immune cells, including neutrophils. Neutrophils express all known TLRs except for TLR3 and TLR7, which recognize double- and single-stranded RNA, respectively (Futosi et al. 2013). Instead, neutrophils express a distinct pattern of RNA recognition receptors such as retinoic acid-inducible gene (RIG-I), melanoma differentiation-associated protein 5 (MDA-5), and TLR8 (Berger et al. 2012). The engagement of TLRs by microbial structures in neutrophils has a priming effect and induces the production of cytokines and chemokines (Cloutier et al. 2007; Futosi et al. 2013). The signaling pathways elicited by TLRs are myeloid differentiation protein 88 (MyD88) dependent or independent; however, the MyD88-independent pathway is not used in human neutrophils (Tamassia et al. 2007). The MyD88 adapter recruits members of the IL-1 receptor-associated kinase (IRAK) family, which are phosphorylated on binding to MyD88, members of the TNF receptor-associated factor (TRAF) family, and the TAK1 kinase. In human LPS-activated neutrophils, TAK1 phosphorylates IκB kinase (IKK), which itself induces the degradation of inhibitor of NF-κB (IκB) proteins and the phosphorylation of nuclear factor NF-kappa-B p65 subunit (p65/RelA); these events enable nuclear factor κB (NF-κB) binding to DNA and lead to gene transcription (Ear et al. 2010). In addition, LPS was found to induce the phosphorylation of p38 MAPK, ERK1/ERK2, mitogen- and stress-activated protein kinase (MSK1), and STAT1 in a TAK1-dependent manner in human neutrophils (Ear et al. 2010; Mayer et al. 2013). Intermediates between TAK1 and MAPKs, however, are still elusive as it was recently found that ERK is activated independently of the MAKP kinase MEK in human neutrophils in response to LPS or peptidoglycan, as opposed to what is found in other cell types (Simard et al. 2015). On the translational side, LPS induces the activation of a class IA PI3K, composed of the p85α and p110δ, and MAP kinase-interacting serine/threonine-protein kinase 1 (MNK1) in human neutrophils (Fortin et al. 2011, 2013). These kinases were found to be downstream of p38 MAPK and TAK1, and their activation led to the phosphorylation of several key molecules involved in protein translation: ribosomal protein S6 (S6), S6 kinase (S6K), and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1).

Few data exist concerning the age-related alterations in TLR signaling in human neutrophils. The distribution of MyD88 and IRAK-1 in lipid rafts (LR), which are microdomains of the plasma membrane enriched in cholesterol, receptors, and signaling molecules (Lorent and Levental 2015), and in LPS-stimulated neutrophils was determined. In neutrophils of young and elderly donors, MyD88 was evenly distributed in LR and non-lipid raft (NLR) fractions of plasma membranes, and LPS stimulation had no effects on MyD88 distribution (Fulop et al. 2004). MyD88 is an adapter protein whose close proximity to the plasma membrane might explain that no changes in its distribution were observed after LPS stimulation. Conversely, the distribution of IRAK-1 is dynamic as it is moving from NLR in resting cells to LR in LPS-activated neutrophils of young donors; with age, however, IRAK-1 is moving in the opposite direction: from LR to NLR (Fulop et al. 2004). For TLR2, no significant changes in distribution were found for both age groups in either resting or LPS-stimulated neutrophils (Fulop et al. 2004). Also, the expression of TLR4 and TLR2 on neutrophils was investigated by flow cytometry, but no changes were found in the percentage of neutrophils expressing TLR4 and TLR2 with age (Fulop et al. 2004). Similar results were obtained when the amount of TLR4 or TLR2 receptors were compared in aging by flow cytometry (Fulop et al. 2004; Hazeldine et al. 2014). A recent study investigated the effects of age in human neutrophils activated with Pam3CSK4, an analog of the immunologically active N-terminal portion of bacterial lipoproteins, which is recognized by TLR1-TLR2 complexes. They reported that although neutrophils from both age groups expressed similar amount of TLR1 and TLR2, the responses to Pam3CSK4 were altered with age (Qian et al. 2014). Indeed, the amount CD11b/CD18 and the degree of CD62L shedding were lower in Pam3CSK4-stimulated neutrophils of elderly donors. In addition, phosphorylation of p38 MAPK was reduced with age, and this caused a decrease in the amount of secreted IL-8 after Pam3CSK4 stimulation (Qian et al. 2014). Also, the Pam3CSK4-induced rescue from apoptosis was decreased in neutrophils of elderly donors. Interestingly, they reported that glucose uptake by neutrophils of elderly donors was strongly reduced after Pam3CSK4 stimulation (Qian et al. 2014). This reduced bioenergetics in neutrophils of elderly donors could be an interesting target for aging research.

Triggering Receptor Expressed on Myeloid Cells-1

TREM-1 receptor is one of the many activating receptors of the Ig family that are expressed on macrophages and neutrophils. TREM-1 is upregulated at the surface of neutrophils and macrophages in inflammatory conditions and LPS-induced sepsis in mice (Bouchon et al. 2000). Because the cytoplasmic tail of TREM-1 is short and devoid of signaling motifs, TREM-1 must associate, through a positively charged residue in its transmembrane region, with an adapter protein named DNAX-activating protein 12 (DAP12) to signal. The ITAM domain of DAP12 is phosphorylated by Rous sarcoma virus proto-oncogene (Src) family kinases, which leads to the activation of the spleen tyrosine kinase (Syk) (Arts et al. 2013). In neutrophils, TREM-1 triggers the production of cytokines and chemokines and of free radicals, degranulation, and phagocytosis (Bouchon et al. 2000; Bleharski et al. 2003; Radsak et al. 2004; Fortin et al. 2007b). The production of free radicals is mediated by p38 MAPK and by PKCθ, whose activation is induced by PI3K and by PLCγ, as p38 MAPK and PLC-γ are responsible for phagocytosis (Arts et al. 2013). The production of cytokines and chemokines is regulated by ERK1/ERK2, JAK-STAT, Akt, and NF-κB (Arts et al. 2013). In neutrophils, stimulation with both TREM-1 and TLR ligands synergized to augment functional responses (Bleharski et al. 2003; Radsak et al. 2004; Fortin et al. 2007b). Thus, dysregulation in TREM-1 signaling with age could worsen the consequences of infection in older adults. Contrary to other TREM family members, TREM-1 does not directly bind to lipids commonly found in cell membranes of prokaryotes and eukaryotes (Cannon et al. 2012). It has been hypothesized, however, that an endogenous ligand for TREM-1 existed on TLR-activated neutrophils (Gibot et al. 2006), and, recently, one such ligand was discovered. Indeed, it was found that peptidoglycan formed a complex with peptidoglycan recognition protein 1 (PGLYRP1) and that this complex then worked as a functional ligand for TREM-1 (Read et al. 2015). In keeping with this, it was reported that TREM-1 and TLR4 co-localized in human neutrophils after stimulation with LPS (Fortin et al. 2007b). Moreover, silencing of TREM-1 in macrophages induced a downregulation in the expression of key signaling molecules of the TLR4 pathway (Ornatowska et al. 2007). Emerging data are showing an unsuspected link between TLRs and TREM-1, and it is possible that TREM-1 ligands are multimeric complexes engaging with various surface receptors (Arts et al. 2013).

So far, there is scarce data on the impact of human aging on TREM-1-induced functions in cells of the immune system. It was reported that neutrophils from elderly donors showed impaired responses following TREM-1 engagement (Fortin et al. 2007c). Notably, TREM-1 could not prime the production of free radicals in neutrophils of elderly donors as it did in neutrophils of young donors (Fortin et al. 2007c). In addition, TREM-1 engagement could not reverse apoptosis following incubation with LPS or GM-CSF in neutrophils of elderly donors (Fortin et al. 2007c). Probably explaining these decreased functions with age, TREM-1 was not recruited to LR after engagement in neutrophils of elderly donors (Fortin et al. 2007c). It was also reported that the phosphorylation of Akt and PLC-γ was decreased with age. Given that TREM-1 is engaged during bacterial and viral infections (Ruiz-Pachecoa et al. 1993), dysregulation of TREM-1-induced functions could be detrimental for older adults suffering inflammatory conditions. Finally, membrane-bound TREM-1 is cleaved during sepsis or infections and circulates in the bloodstream. Levels of soluble TREM-1 in the serum are a useful diagnostic marker of inflammatory conditions (Gibot et al. 2004; Ruiz-Pacheco et al. 2014), and it is currently unknown whether aging is influencing this. This could be relevant since a dysregulated shedding of TREM-1 could lead to the erroneous diagnostic of inflammatory conditions in elderly patients.

Conclusion

Neutrophils are important innate cells of the immune system and protect the body against invading organisms and pathogens. They are not only part of the first line of defense but can also modulate the adaptive immune response. Alterations in receptor-mediated functions, including the production of free radicals, chemotaxis, and apoptosis/survival, of neutrophils with age have been amply documented. These and other consequences of aging on human neutrophils may impair the activation of immune responses and contribute to poorer vaccine responses and greater morbidity and mortality from infectious diseases in older adults.

Altogether, studies done on signaling pathways elicited by the engagement of various receptors strongly suggest that signal transduction is altered with age in human neutrophils. In addition, both positive and negative signaling events seem to be altered. These alterations are not generally arising from a change in receptor numbers, but are probably related to changes in the physicochemical composition of plasma membranes with age. It has been shown that changes in membrane fluidity affect chemotaxis and the production of free radicals in neutrophils (Alvarez et al. 2001). An age-dependent decrease in plasma membrane fluidity has been shown in various cell types (Rivnay et al. 1980; Shinitzki 1987), including T cells (Larbi et al. 2004a, b); conversely, in human (Fulop et al. 2004) and rat (Alvarez et al. 2001) neutrophils, increases in membrane fluidity were reported. These data show that an increase or a decrease in plasma membrane fluidity with age is deleterious for cellular functions. The presence of LR in neutrophils has been described, and it was suggested that LR play an important role for signal transduction and cell functions (Simons and Ikonen 1997; Kindzelskii et al. 2004; Sitrin et al. 2004; Fortin et al. 2007b, c; Fortin and Fulop 2015). It was reported that the recruitment of TLRs and TREM-1 to LR was altered in human neutrophils with age. Whether the increased plasma membrane fluidity observed in aging is responsible for this is currently unknown. In T cells, age-related deficiencies in cholesterol exchange were reported; moreover, these deficiencies may explain the increased concentrations of cholesterol in plasma membranes and the altered LR recruitment of signaling molecules in T cells of elderly donors (Larbi et al. 2014). In aged rat neutrophils, however, it was found that the cholesterol content did not change but that the phospholipid content was increased (Alvarez et al. 2001). Also, age-related changes in actin cytoskeleton functions were suggested to cause alterations in signaling pathways (Rao et al. 1992). Thus, age-related changes in the composition of cell membrane seem to alter its functional properties, and this, in turn, affects the signal transduction of key signaling pathways in neutrophils. These changes should be taken into account if novel therapeutic approaches are to be designed with the aim to restore or increase immune responses in older adults.

Notes

Acknowledgments

We apologize to members of the scientific community whose contributions could not be cited. This work was supported by a grant-in-aid from the National Science and Engineering Research Council of Canada (No 249549), Research Center on Aging of Sherbrooke, the ImAginE Consortium, and the Canadian Institute of Health Research (No 63149).

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Carl Fortin
    • 1
    Email author
  • Tamas Fulop
    • 1
  • Anis Larbi
    • 2
  • Gilles Dupuis
    • 3
  1. 1.Division of Geriatric Medicine, Department of Medicine, Research Center on AgingUniversité de SherbrookeSherbrookeCanada
  2. 2.Singapore Immunology Network (SIgN), Aging and Immunity ProgramAgency for Science Technology and Research (A*STAR)SingaporeSingapore
  3. 3.Immunology Programme, Department of Biochemistry, Faculty of Medicine and Health SciencesUniversity of SherbrookeSherbrookeCanada

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