Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

FPR2/ALX

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_590

Synonyms

Historical Background

The FPR2/ALX receptor is a member of the formyl peptide receptor (FPR) superfamily which in humans also includes formyl peptide receptor 1 (FPR1) and formyl peptide receptor 3 (FPR3). Recent interest in this specific receptor reflects its intriguing anti-inflammatory and proresolving bioactions in contrast to other FPR family members (Serhan 2007; Maderna et al. 2010). FPR2/ALX was identified as a specific receptor for lipoxin A4 (LXA4) in 1992 (Fiore et al. 1992). Using radiolabeled [11,12-3H]LXA4 and human polymorphonuclear leukocytes (PMNs) in which LXA4-mediated action had previously been identified, specific stereoselective binding with a Kd of approximately 0.5 nM was demonstrated. Modulation of [11,12-3H]LXA4 binding by guanosine analogs indicated that this binding site was a G-protein-coupled receptor (GPCR). Screening of orphan receptors in differentiated HL-60 cells, which displayed specific LXA4 binding, was carried out in parallel and it identified a GPCR with high affinity for and selective binding by [11,12-3H](6R)-LXA4. Leukotriene B4 (LTB4), lipoxin B4 (LXB4), (6S)-LXA4, or 11-trans-LXA4 did not compete with LXA4 for binding of this orphan receptor when expressed in CHO cells, indicating specificity for LXA4. LXA4 stimulated GTPase activity and promoted the release of esterified arachidonate in this model system. A pertussis toxin sensitive response further supported the hypothesis that the cDNA encoded a GPCR. The receptor cDNA sequence was found to be ~70% homologous to FPR1 and was thus named formyl peptide receptor-like1 (FPRL1) (for more detail refer to Chiang et al. 2006; Ye et al. 2009). It has also been referred to by a number of other names in the literature (see synonyms). In accordance with the International Union of Basic and Clinical Pharmacology (IUPHAR) nomenclature 2009 (Ye et al. 2009), this receptor is referred as FPR2/ALX in this entry. FPR2/ALX was subsequently identified and cloned in several cell types including monocytes, T cells, synovial fibroblasts, and intestinal epithelial and renal mesangial cells. The gene encoding FPR2/ALX is located at 19q13.3 and is a single copy gene with an intronless open reading frame (for more detail refer to Chiang et al. 2006; Ye et al. 2009). FPR2/ALX is now known to bind endogenous and exogenous proteins and lipid ligands eliciting distinct proinflammatory or anti-inflammatory responses indicating that FPR2/ALX can thus serve as a stereoselective multirecognition receptor in immune responses (Maderna et al. 2010).

FPR2/ALX Expression, Structure, and Agonists

FPR2/ALX is expressed in cells of diverse lineage: myeloid, epithelial, and mesenchymal. Upregulation of FPR2/ALX by proinflammatory cytokines (e.g., tumor necrosis factor-a [ TNF Alpha-Induced Protein 3]) suggests the regulation of the receptor under inflammatory conditions. Additionally, upregulation of FPR2/ALX expression by anti-inflammatory glucocorticoid-stimulated signaling in human PMNs and monocytes as well as murine dermal tissues is thought to contribute to their potent anti-inflammatory effects (Perretti and D’Acquisto 2009).

FPR2/ALX is a 351 amino acid protein, the overall homology between human, mouse, and rat FPR2/ALX is 74% at nucleotide and 65% at the amino acid sequence level. One hundred percent homology across these species is found in the second intracellular loop, 97% homology in the sixth transmembrane domain (TMD), followed by the second, third, and seventh TMD as well as the first extracellular loop (87–89%). ChemR23 is a GPCR which like FPR2/ALX binds both peptide and lipid ligands and is implicated in anti-inflammatory signal transduction. ChemR23 shares 36.4% overall homology with FPR2/ALX amino acid sequence. It has been suggested that highly conserved domains within the second intracellular loop and the seventh TMD which share 75% and 69.5% identity with FPR2/ALX, respectively, may contribute to their anti-inflammatory and proresolving properties. Such conservation between species and among similar receptors suggests these regions of the receptor play an essential role in ligand recognition and functional G-protein coupling. Studies using chimeric receptors show that the seventh TMD and its adjacent regions are essential for LXA4 recognition. Ser-236, Ser-237, and Tyr-302 are essential for LXA4-stimulated FPR2/ALX signaling and a role for conserved glycosylation sites present on Asn-4 and Asn-179 are important for peptide binding (for more detail refer to Chiang et al. 2006). The ability of FPR2/ALX to interact with ligands of diverse structural and chemical nature (i.e., lipid, peptide, protein) is thought to be related to certain properties within its binding pocket, which is large enough to accommodate ligands like the protein Annexin A1 (AnxA1) (~40 kDa), yet flexible enough to contact the smaller peptide ligands like the synthetic proinflammatory peptide WKYMVm. Hydrophobic interactions and possibly multiple ligand-binding sites may also facilitate interaction with both peptide and lipid agonists (for more detail refer to Ye et al. 2009). FPR2/ALX agonists elicit either proinflammatory or anti-inflammatory responses depending on the ligand and cell type. The bacterial peptide N-formyl-methionine-leucine-phenylalanine (fMLF) is one of the smallest and most potent formyl peptides and one of the first identified chemotactic peptides. Although FPR2/ALX shows low affinity for fMLF (Kd = 430 nM) compared to FPR1 (Kd = 1 nM), it does show high affinity for mitochondrial derived formyl peptides as well as several Listeria monocytogenes–derived formyl peptides (for more detail refer to Ye et al. 2009). It is hypothesized that during inflammation, impaired mitochondrial function results in N-formyl peptide secretion which attracts inflammatory cells to the site of tissue damage (Godson et al. 2000). In vitro studies show that a number of mitochondrial N-formylated peptides are agonists at FPR2/ALX. Some of these naturally produced peptides interact with FPR2/ALX in the nanomolar to subnanomolar range. FPR2/ALX also shows affinity for nonformylated peptides such as major histocompatibility complex (MHC)–binding peptide, a potent necrotactic peptide derived from mitochondrial NADH dehydrogenase subunit 1, which competes with [3H]LXA4 for FPR2/ALX binding and stimulates PMN chemotaxis (Chiang et al. 2000).

A number of FPR2/ALX ligands have antimicrobial properties and are stored in human neutorphil granules. LL-37 is expressed by leukocytes and epithelial cells and secreted into wounds and onto the airway surface where it attracts monocytes, neutrophils, and T lymphocytes through FPR2/ALX activation (for more detail refer to Ye et al. 2009). LL-37-stimulated release of proinflammatory LTB4 from PMNs is inhibited by LXA4 (Wan et al. 2011). Temporin A, a frog-derived antimicrobial peptide also acts through FPR2/ALX, stimulating monocyte, macrophage, and neutrophil migration. Nonformylated peptides from Helicobacter pylori attract monocytes and basophils to the gastric mucosa and those from human immunodeficiency virus-1 (HIV-1) activate phagocytic leukocytes through their agonistic activity at FPR2/ALX (for more detail refer to Ye et al. 2009). Furthermore, FPR2/ALX has been shown to recognize phenol-soluble modulin produced by strains of highly pathogenic Staphylococcus aureus and to initiate a proinflammatory neutrophil response (Rautenberg et al. 2011).

Host-derived peptides signaling through FPR2/ALX have been associated with inflammatory and amyloidogenic diseases. Serum amyloid A (SAA) is an acute-phase protein best known for its role in the pathogenesis of inflammatory arthritis. SAA serum concentrations increase dramatically in response to infection, trauma, and other physiological stress and it acts through FPR2/ALX to promote chemotaxis of monocytes, neutrophils, mast cells, and T lymphocytes to the wounded area. SAA is also known to induce matrix metalloproteinase expression in fibroblast-like synoviocytes and monocytes and this activity is mimicked by the proinflammatory peptide and FPR2/ALX agonist WKYMVm (for more detail refer to Ye et al. 2009). Aβ42 the 42 amino acid peptide cleavage product of the β-amyloid peptide, is implicated in the pathology of Alzheimer’s disease. FPR2/ALX mediates Aβ42-stimulated activation and accumulation of monocytic phagocytes as well as facilitating Aβ42 uptake, thus contributing to fibrillar formation (Cui et al. 2002). Humanin is an endogenous neuroprotective peptide which displays increased potency at FPR2/ALX when N-formylated. Humanin may competitively inhibit Aβ42 at FPR2/ALX. Other proinflammatory FPR2/ALX ligands include truncated chemotactic peptides (e.g., CKβ8-1), a urokinase-type plasminogen activator receptor fragment and prion protein (Ye et al. 2009).

FPR2/ALX ligands which display anti-inflammatory properties are of particular interest. AnxA1 is a glucocorticoid-inducible protein and FPR2/ALX agonist which is expressed by a wide range of immune cells and tissues. Following cellular activation, AnxA1 is mobilized to the cell surface and secreted, where it colocalizes with FPR2/ALX. AnxA1 and AnxA1 peptide derivatives have been shown to inhibit neutrophil adhesion and transmigration through endothelial barriers both in vitro and in vivo. Additionally, increased secretion of the anti-inflammatory cytokine, interleukin-10 (IL-10), in response to AnxA1 exposure has been described (Perretti and D’Acquisto 2009). Endogenous AnxA1 and peptide derivatives are released from apoptotic cells and act on macrophages to promote efferocytosis of apoptotic leukocytes (Scannell et al. 2007). Interestingly, it has been shown that LXA4 and Antiflammin-2, the FPR2/ALX peptide agonist, which corresponds to the region 246–254 of AnxA1, also provoke FPR2/ALX-dependent mobilization of AnxA1 to the plasma membrane of PMNs (Brancaleone et al. 2011).

LXA4 was the first identified endogenous ligand described for FPR2/ALX. Unlike the diverse array of peptide ligands for FPR2/ALX discussed so far, lipoxins (LXs) are arachidonate-derived lipid mediators. LXs are generated in vivo within an inflammatory milieu where they possess anti-inflammatory activity as well as the ability to promote the resolution of inflammation. LXA4 displays multilevel control of processes relevant in acute inflammation via specific and selective actions on multiple cell types through specific receptors (Serhan 2007). Well-established effects of LXA4 include limiting of leukocyte infiltration, inhibition of neutrophil and eosinophil activation, stimulation of efferocytosis of apoptotic leukocytes by macrophages as well as stimulation of genes which promote inflammatory resolution (reviewed in Maderna and Godson 2009). In vitro studies have shown that LXA4 inhibits production of proinflammatory cytokines in synovial fibroblasts and intestinal and bronchial epithelial cells (for more detail refer to Ye et al. 2009). Furthermore, LXA4 stimulates the expression of anti-inflammatory IL-10 in endothelial cells (Baker et al. 2009). More recently, LXA4 has been shown to have antifibrotic activity in experimental models of lung and kidney fibrosis as will be discussed later (Rodgers et al. 2005; Wu et al. 2006; Martins et al. 2009; Borgeson et al. 2011).

Aspirin-triggered lipoxins (ATLs) such as 15-epi-LXA4 are generated by the activity of aspirin-acetylated cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO). 15-epi-LXA4 displays similar activity to native LXA4 and acts with higher affinity for and potency at FPR2/ALX. Given the rapid metabolic degradation of native LXA4, several generations of analogs have been synthesized. These include a new class of chemically stable LX analogs featuring replacement of the tetraene unit of native LXA4 with a substituted benzo-fused ring. These benzo-LXs have also been shown to have potent anti-inflammatory properties that are likely to be mediated through FPR2/ALX (O’Sullivan et al. 2007; Sun et al. 2009).

Recent investigations using mice deficient in the murine homologue of FPR2/ALX have provided important insights into this receptor. In experimental models the animals showed exaggerated inflammatory responses to arthrogenic stimuli (Dufton et al. 2010). Bone marrow–derived macrophages from these mice were unable to phagocytose apoptotic PMNs in response to stimulation with LXA4 or Ac2-26 (Maderna et al. 2010). These data highlight the role of FPR2/ALX as an anti-inflammatory and proresolution receptor in the context of LXA4 or AnxA1 stimulation. It is now appreciated that the murine FPR2/ALX homologues targeted in these models may also have deleted Fpr3.

Resolvin D1 (RvD1), like LXA4, is generated during the resolution phase of inflammation and also displays potent and stereoselective anti-inflammatory actions. Using [3H-RvD1], FPR2/ALX was identified as one of two specific RvD1 recognition sites. RvD1 increased macrophage phagocytosis of apoptotic PMNs and its ability to do so was enhanced by overexpression of FPR2/ALX and GPR32, the orphan receptor identified to bind RvD1 (Krishnamoorthy et al. 2010).

The potential of computational platform design to identify novel, potent FPR2/ALX agonists with anti-inflammatory and cardioprotective effects has been demonstrated using inflamed air pouch and myocardial ischemia-reperfusion-injury (IRI) in rodent models (Hecht et al. 2009).

Antagonists of the formyl peptide receptor family include t-Boc which was developed by replacing the N-formyl group of fMLF with a tertiary butyloxycarbonyl. Similar antagonists include Boc1 and Boc2 which act at high micromolar concentrations to partially inhibit FPR2/ALX. Selective antagonists for FPR2/ALX like WRWWWW have been identified through screening hexapeptide libraries for the ability to inhibit binding of a synthetic peptide agonist, WKYMVm to FPR2/ALX (for more detail refer to Ye et al. 2009) and as described above FPR2/ALX knockout mice have been developed for in vivo studies (Dufton et al. 2010).

FPR2/ALX Signal Transduction

FPR2/ALX is phosphorylated in response to ligand activation, but as of yet little is known about the kinase(s) involved in the process. Lipid rafts are known to play an important role in receptor coupling to G-proteins and FPR2/ALX signaling is sensitive to cholesterol depletion in PMNs. Although the current understanding of the downstream signaling following FPR2/ALX activation remains incomplete, it does appear that the nature of signaling elicited is dependent on the ligand concentration and cell type in which FPR2/ALX is activated (for more detail refer to Chiang et al. 2006; Ye et al. 2009).

Proinflammatory responses mediated by FPR2/ALX include the activation of nuclear factor-κB ( NF-κB Family) by SAA in human neutrophils resulting in interleukin-8 (IL-8) secretion (He et al. 2003). SAA induces neutrophil Ca2+ mobilization and activation of ERK1/2 and p38. SAA also promotes the survival of neutrophils by delaying apoptosis. The underlying mechanism is thought to involve SAA activation of ERK1/2 and Akt which in turn leads to downstream phosphorylation events which regulate apoptosis (El Kebir et al. 2008).

The signaling pathways involved in the anti-inflammatory and proresolving effects of FPR2/ALX agonists are of great interest. LXA4 and ATLs suppress the expression of neutrophil and endothelial adhesion molecules and thus attenuate adhesion and the production of proinflammatory cytokines through modulation of MAPK signaling, superoxide generation, and  NF-κB activity (Filep et al. 2005). LXA4 stimulates the non-phlogistic uptake of apoptotic PMNs by monocyte-derived macrophages (Godson et al. 2000; Mitchell et al. 2002) by a process coupled to Rho- and Rac-dependent cytoskeletal rearrangement (Maderna et al. 2002). In human enterocytes, ATL analogs downregulate Salmonella typhimurium–induced gene expression (Gewirtz et al. 1998). A subset of these genes are known to be regulated by the transcription factor  NF-κB through a FPR2-/ALX-dependent mechanism (for more detail refer to Chiang et al. 2006). LXA4 and ATLs attenuate nuclear accumulation of  NF-κB and AP-1 transcription factors in human leukocytes thus inhibiting LPS-induced IL-8 secretion. Mesangial cell proliferation is a feature of glomerular inflammation and LXA4 inhibits LTD4-stimulated mesangial proliferation (McMahon et al. 2000). The underlying mechanisms involve LXA4’s inhibition of LTD4-stimulated platelet-derived growth factor (PDGF) receptor transactivation (McMahon et al. 2002). LXA4 and Ac2-26 attenuated PDGFRß phosphorylation but did not alter the receptor tyrosine kinase activity, suggesting the involvement of protein tyrosine phosphatases. Using cells stably transfected with FRP2/ALX, transient transfection with PDGFRβ and stimulation with PDGF-BB resulted in a decrease in PDGFRβ phosphorylation compared to control cells. These data confirmed that the reduced phosphorylation was FPR2/ALX dependent. LXA4 was shown to promote SHP-2-mediated dephosphorylation of PDGFRβ. Site-directed mutagenesis of the cytoplasmic domain of PDGFRβ indicated the importance of the binding site of the p85 subunit of  PI3K in LXA4-mediated transinactivation of the receptor (Mitchell et al. 2007). LXA4 has also been shown to inhibit epidermal growth factor (EGF) receptor and vascular endothelial growth factor (VEGF) receptor 2 activation (Baker et al. 2009). These studies highlighted the complex cross talk between GPCRs and receptor tyrosine kinases in an inflammatory milieu and suggested a protective role for LXA4 in renal inflammation and fibrosis in which activation of the PDGFRβ is known to play a pathological role (Mitchell et al. 2007). Additionally LXA4 inhibits TNF-α induced mesangial cell proliferation (Wu et al. 2005).

The best characterized mechanism of FPR2/ALX internalization is described following stimulation with a synthetic proinflammatory peptide agonist WKYMVm and results in lipid raft–dependent, clathrin-mediated FPR2/ALX endocytosis. However it has recently been shown that when stimulated with anti-inflammatory ligands, FPR2/ALX colocalizes with caveolin-1 and flotillin-1 but not clathrin and that internalization of FPR2/ALX is required for LXA4 and Ac2-26 stimulated macrophage phagocytic activity and is dependent on PKC (for more detail refer to Ye et al. 2009; Maderna et al. 2010).

FPR2/ALX: Anti-inflammatory, Proresolution, and Therapeutic Potential

As outlined, FPR2/ALX agonists have been shown to modulate specific actions of cells involved in immune-inflammatory responses and thus FPR2/ALX has been proposed as a target for therapeutic intervention. Several experimental models of disease further support this idea.

Transgenic mice with myeloid-selective expression of human FPR2/ALX (generated by DNA injection of 3.8 kb transgene consisting of full-length human FPR2/ALX cDNA driven by a fragment of human CD11b promoter) were challenged via dermal ear skin with proinflammatory LTB4 and prostaglandin E2 (PGE2). The FPR2/ALX transgenic mice showed a significant reduction in neutrophil infiltration compared to nontransgenic littermate controls. In a model of zymosan-induced peritonitis, transgenic mice exhibited a reduced level of neutrophil infiltration and increased sensitivity to i.v. administration of 15-epi-LXA4 (Devchand et al. 2003).

The potential of LXA4 as a therapeutic mediator has been demonstrated in numerous animal models including a variety of renal injury models, inflammatory skin conditions, inflammatory intestinal disorders, lung injury, and asthma. Of particular interest in the context of Alzheimer’s disease, LXA4 has been shown to attenuate Aβ42-induced expression of proinflammatory cytokines, interleukin-1β (IL-1β) and  TNFα, to inhibit the degradation of IκBa and the translocation of  NF-κB p65 subunit into the nucleus in the cortex and hippocampus of mice (Wu et al. 2011). An orally stable LX analog ZK-192 has been shown to have antiinflammatory activity in vivo (Guilford et al. 2004). The chronic perpetuation of an inflammatory response can result in fibrosis and eventual organ failure. The antifibrotic actions of LXA4 and a synthetic-LX analog have been demonstrated in a murine model of early renal fibrosis. LXs attenuated collagen deposition and renal apoptosis and shifted the inflammatory cytokine milieu toward resolution by inhibiting  TNF-α and IFN-γ expression, while stimulating proresolving IL-10. LXs attenuated unilateral ureteric obstruction–induced activation of  MAP kinases, Akt, and Smads in injured kidneys. Further analysis suggests that renal fibroblast responses to TGF-β1 may be among the targets of LXA4 in this context (Borgeson et al. 2011). Furthermore, the antifibrotic activity of an ATL analog has been demonstrated in bleomycin-induced lung injury (Martins et al. 2009).

In murine models of IRI, FPR2/ALX ligands have been shown to have protective effects. Hundred microgram of Ac2-26, 30 min prior to renal artery clamping was shown to be effective at preventing loss of glomerular filtration rate and decreases in urinary osmolarity as well as protecting against the development of acute tubular necrosis, preventing neutrophil extravasation, and attenuating macrophage infiltration as well as affording structural protection against IRI. In vitro ischemia-reperfusion studies using isolated proximal tubules from control mice with no inflammatory cell influence showed that Ac2-26 protected against IRI. It has been proposed that this indicates that the protective effects are directly related to the intracellular actions of this peptide in tubular epithelial cells and suggest an important role for AnxA1 in renal epithelial cell defense against IRI (Facio et al. 2011). Analogous to findings with Ac2-26, a synthetic analog of 15-epi-LXA4, 15-epi-16-(para-fluorophenoxy)-LXA4-methyl ester was shown to be protective against murine renal IRI (Leonard et al. 2002).

Compound 43, a nitrosylated pyrazolone derivative, was identified as a FPR2/ALX agonist in a high-throughput compound library screen. It was found to inhibit PMN migration and to have good solubility characteristics and bioavailability following i.v. administration to rats. In a murine model of prostaglandin E2 and LTB4 induced ear inflammation, oral administration of Compound 43 (50 mg/kg) 1 h before induction of inflammation afforded protection from edema which was comparable to established therapy (i.e., dexamethasone, 1 mg/kg i.v.) (Burli et al. 2006).

Together, these in vivo studies using a number of molecules known to be FPR2/ALX agonists make a convincing argument for targeting this receptor for therapeutic purposes in a diverse range of inflammatory conditions. The development of stable and potent FPR2/ALX agonists makes it an even more attractive target. Recent developments have shown that human PMN-derived microparticles contain precursors for proresolving lipid mediator biosynthesis and display anti-inflammatory properties via FPR2/ALX. Using microparticle scaffolds, nanoparticles containing aspirin-triggered RvD1 or a stable analog of LXA4, o-[9,12]-benzo-ω6-epi-LXA4 have been developed. These enriched nanoparticles dramatically reduce PMN influx in murine zymosan–induced peritonitis, accelerate keratinocyte wound healing, and protect against inflammation in the temporomandibular joint (Norling et al. 2011).

Summary

Since its identification in 1992, FPR2/ALX has been shown to be a receptor with the ability to interact with a diverse array of ligands and to transduce signals which elicit completely contrasting physiological responses, which are either proinflammatory or anti-inflammatory in nature. Precise mechanisms through which differential responses are mediated remain incompletely understood. Yet this promiscuous receptor continues to attract research interest as a possible therapeutic target. Future studies will reveal the true potential of FPR2/ALX in anti-inflammatory and proresolving circuits where its modulation may help restore tissue homeostasis and prevent fibrosis, the common, progressive pathologic feature of numerous inflammatory conditions.

Notes

Acknowledgments

The authors thank Dr. Aisling Kennedy and Dr. Eoin Brennan for their helpful comments. Work in the authors’ lab is funded by Science Foundation Ireland, The Health Research Board, and The Government of Ireland Programme for Research in Third-Level Institutions. Karen Nolan is an IRCSET postgraduate Scholar.

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.UCD Diabetes Research Centre, UCD Conway InstituteSchool of Medicine and Medical Sciences, University College DublinDublinIreland