Biology:Formyl peptide receptor 2

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Short description: Protein-coding gene in the species Homo sapiens

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

N-formyl peptide receptor 2 (FPR2) is a G-protein coupled receptor (GPCR) located on the surface of many cell types of various animal species. The human receptor protein is encoded by the FPR2 gene and is activated to regulate cell function by binding any one of a wide variety of ligands including not only certain N-Formylmethionine-containing oligopeptides such as N-Formylmethionine-leucyl-phenylalanine (FMLP) but also the polyunsaturated fatty acid metabolite of arachidonic acid, lipoxin A4 (LXA4) and long chain Ceramide .[1][2][3] Because of its interaction with lipoxin A4, FPR2 is also commonly named the ALX/FPR2 or just ALX receptor.

Nomenclature

Confusingly, there are two "standard" nomenclatures for FPR receptors and their genes, the first used, FPR, FPR1, and FPR2 and its replacement, FPR1, FPR2 (this gene), and FPR3. The latter nomenclature is recommended by the International Union of Basic and Clinical Pharmacology[4] and is used here. Other previously used names for FPR1 are NFPR, and FMLPR; for FPR2 are FPRH1, FPRL1, RFP, LXA4R, ALXR, FPR2/ALX, HM63, FMLPX, and FPR2A; and for FPR3 are FPRH2, FPRL2, and FMLPY.[4]

Gene

Human

The human FPR2 gene encodes the 351 amino acid receptor, FPR2, within an intronless open reading frame. It forms a cluster with FPR1 and FPR3 genes on chromosome 19q.13.3 in the order of FPR1, FPR2, and FPR3; this cluster also includes the genes for two other chemotactic factor receptors, the G protein-coupled C5a receptor (also termed CD88) and a second C5a receptor, GPR77 (i.e. C5a2 or C5L2), which has the structure of G protein receptors but apparently does not couple to G proteins and is of uncertain function.[5] The FPR1, FPR2, and FPR3 paralogs, based on phylogenetic analysis, originated from a common ancestor with early duplication of FPR1 and FPR2/FPR3 splitting with FPR3 originating from the latest duplication event near the origin of primates.[6]

Mouse

Mice have no less than 7 FPR receptors encoded by 7 genes that localize to chromosome 17A3.2 in the following order: Fpr1, Fpr-rs2 (or fpr2), Fpr-rs1 (or LXA4R), Fpr-rs4, Fpr-rs7, Fpr-rs7, Fpr-rs6, and Fpr-rs3; this locus also contains Pseudogenes ψFpr-rs2 and ψFpr-rs3 (or ψFpr-rs5) which lie just after Fpr-rs2 and Fpr-rs1, respectively. The 7 mouse FPR receptors have ≥50% amino acid sequence identity with each other as well as with the three human FPR receptors.[7] Fpr2 and mFpr-rs1 bind with high affinity and respond to lipoxins but have little or no affinity for, and responsiveness to, formyl peptides; they thereby share key properties with human FPR2;[8][9][10]

Rat

Rats express an ortholog of FPR2 (74% amino acid sequence identity) with high affinity for lipoxin A4.[7]

Expression

The FPR2 receptor is expressed on human neutrophils, eosinophils, monocytes, macrophages, T cells, synovial fibroblasts, and intestinal and airway epithelium.[11]

FPL2 is often co-expressed with FPR1. It is widely expressed by circulating blood neutrophils, eosinophils, basophils, and monocytes; lymphocyte T cells and B cells; tissue Mast cells, macrophages, fibroblasts, and immature dendritic cells; vascular endothelial cells; neural tissue glial cells, astrocytes, and neuroblastoma cells; liver hepatocytes; various types of epithelial cells; and various types of multicellular tissues.[7][12][13][14][15]

Function

Many oligopeptides with an N-Formylmethionine N-terminal residue—such as the prototypical tripeptide N-Formylmethionine-leucyl-phenylalanine (FMLP)—are products of bacterial protein synthesis. These formylated peptides stimulate granulocytes to migrate directionally (see chemotaxis), and to engage in phagocytosis and bacterial killing, thereby contributing to host defense by directing the innate immune response during acute inflammation.

Early studies indicated that these peptides act through a receptor-mediated mechanism. To investigate this, researchers used the human leukocyte cell line HL-60, which consists of promyelocytes that do not respond to FMLP. Upon differentiation into granulocytes, which do respond, the cells were used to partially purify[16] and clone a gene. When this gene was transfected into FMLP-unresponsive cells, it conferred responsiveness to FMLP and other N-formyl oligopeptides.[17][18][19][20][21] This receptor was initially named the formyl peptide receptor (FPR). Subsequently, two additional genes were cloned, encoding receptor-like proteins with high sequence similarity to FPR.[22][23][24] These three receptors were initially named inconsistently but are now designated formyl peptide receptor 1 (FPR1), formyl peptide receptor 2 (FPR2; this gene), and formyl peptide receptor 3 (FPR3). FPR2 and FPR3 are grouped with FPR1 based on sequence homology, not ligand specificity.

Indeed, FPR2 exhibits markedly different ligand preferences and biological functions compared to FPR1, while FPR3 does not bind FMLP or most other N-formyl peptides that activate FPR1 or FPR2.[4] A major function of FPR2 is to bind certain specialized pro-resolving mediators (SPMs)—including lipoxin (Lx)A4, AT-LxA4 (arachidonic acid metabolites), and resolvin D1 (RvD1), RvD2, and AT-RvD1 (derived from docosahexaenoic acid)—and to mediate their inflammation-resolving effects. In addition, FPR2 also responds to a wide range of peptides and proteins that may promote inflammation or regulate unrelated processes. The physiological role of FPR3 remains unclear.

Knockout studies

The large number of mouse compared to human FPR receptors makes it difficult to extrapolate human FPR functions based on genetic (e.g. gene knockout or forced overexpression) or other experimental manipulations of the FPR receptors in mice. In any event, combined disruption of the Fpr2 and Fpr3 genes causes mice to mount enhanced acute inflammatory responses as evidenced in three models, intestine inflammation caused by mesenteric artery ischemia-reperfusion, paw swelling caused by carrageenan injection, and arthritis caused by the intraperitoneal injection of arthritis-inducing serum.[25] Since Fpr2 gene knockout mice exhibit a faulty innate immune response to intravenous listeria monocytogenes injection,[26] these results suggest that the human FPR2 receptor and mouse Fpr3 receptor have equivalent functions in dampening at least certain inflammatory response.

Endogenous ligands

FPR2, also known as the LXA4 receptor or ALX/FPR2, was initially identified as a high-affinity receptor for the arachidonic acid metabolite lipoxin A4 (LXA4). It was later found to also bind the related metabolites aspirin-triggered lipoxin A4 (ATL, or 15-epi-LXA4), and the docosahexaenoic acid derivative resolvin D1 (RvD1). These three lipid mediators act to inhibit and resolve inflammation.[27][28][29][30][31]

Originally classified as an orphan receptor and termed RFP, FPR2 was discovered by screening myeloid cell-derived libraries using a formyl-methionyl-leucyl-phenylalanine (FMLP)-like probe.[18][23][32]

In addition to LXA4, ATL, RvD1, and FMLP, FPR2 interacts with a wide range of polypeptides, proteins, and their derivatives. These ligands contribute to processes beyond inflammation, including obesity, neurodegeneration, reproduction, and cancer.[33] Nevertheless, FPR2 is best known for mediating the anti-inflammatory and pro-resolving actions of lipoxins and resolvins.[34][35]

A partial list of FPR2/ALX ligands and their proposed inflammatory effects (based on in vitro and animal studies) includes:

  • Bacterial and mitochondrial N-formyl peptides such as FMLP – pro-inflammatory (though possibly less physiologically significant than lipid-derived ligands);
  • Hp(2–20), from Helicobacter pylori – pro-inflammatory;
  • HIV-1-derived peptides: T21/DP107 and N36 (from gp41), F peptide (from gp120), and V3 peptide (from the MN strain) – unknown effects;
  • CCL23β (amino acids 22–137), a splice variant of CCL23, and SHAAGtide, a proteolytic product – pro-inflammatory;
  • Annexin A1-derived peptides (Ac2–26 and Ac9–25) – dose-dependent; anti-inflammatory at low concentrations, pro-inflammatory at high concentrations;
  • Amyloid β(1–42) and PrP(106–126) (from prion protein) – pro-inflammatory, suggesting roles in Alzheimer's disease, Parkinson's disease, Huntington's disease, and prion diseases such as Creutzfeldt–Jakob disease and Kuru;
  • Humanin, a neuroprotective peptide – anti-inflammatory, counteracting amyloid-induced inflammation;
  • Cleaved fragments of UPARAP (uPAR): D2D3(88–274) and uPAR(84–95) – pro-inflammatory;
  • Antimicrobial peptides: LL-37 and CRAMP (human/rat cathelicidins), Pleurocidins (from fish), and Temporin A (frog-derived) – pro-inflammatory;[15]
  • Pituitary adenylate cyclase-activating polypeptide 27 – pro-inflammatory;[4][36]
  • Long-chain ceramides (C14–C20) – bind FPR2 in beige and brown adipocytes to inhibit thermogenesis.[1]

Anti-inflammatory drugs

Dual and selective FPR2 Agonists in clinical development:[37]

  • ACT-389949: A small-molecule FPR2 agonist that has completed phase 1 clinical trials
  • BMS-986235: Another FPR2 agonist in phase 1 trials, with evidence of resolving cardiac inflammation and improving cardiac function in preclinical models.
  • BLXA4 (Methyl ester-benzo-lipoxin A4): An LXA4 analog tested in phase 1 clinical trials for gingival inflammation, shown to reduce local inflammation.

Rezuforimod is a potent and selective FPR2 agonist that inhibits neutrophil adhesion and exhibits broad anti-inflammatory activity.[38]

See also

References

  1. ↑ 1.0 1.1 "Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis". Science 388 (6746). 2025-03-13. doi:10.1126/science.ado4188. PMID 40080544. Bibcode: 2025Sci...388o4188L. 
  2. ↑ "Lipoxin A4 stable analogs are potent mimetics that stimulate human monocytes and THP-1 cells via a G-protein-linked lipoxin A4 receptor". The Journal of Biological Chemistry 272 (11): 6972–6978. Mar 1997. doi:10.1074/jbc.272.11.6972. PMID 9054386. 
  3. ↑ "Entrez Gene: FPR2 formyl peptide receptor 2". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=2358. 
  4. ↑ 4.0 4.1 4.2 4.3 "International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family". Pharmacological Reviews 61 (2): 119–161. Jun 2009. doi:10.1124/pr.109.001578. PMID 19498085. 
  5. ↑ "C5L2: a controversial receptor of complement anaphylatoxin, C5a". FASEB Journal 27 (3): 855–864. Mar 2013. doi:10.1096/fj.12-220509. PMID 23239822. 
  6. ↑ "Adaptive evolution of formyl peptide receptors in mammals". Journal of Molecular Evolution 80 (2): 130–141. Feb 2015. doi:10.1007/s00239-015-9666-z. PMID 25627928. Bibcode: 2015JMolE..80..130M. 
  7. ↑ 7.0 7.1 7.2 "Formyl peptide receptors: a promiscuous subfamily of G protein-coupled receptors controlling immune responses". Cytokine & Growth Factor Reviews 17 (6): 501–519. Dec 2006. doi:10.1016/j.cytogfr.2006.09.009. PMID 17084101. 
  8. ↑ "Functional characterization of three mouse formyl peptide receptors". Molecular Pharmacology 83 (2): 389–398. Feb 2013. doi:10.1124/mol.112.081315. PMID 23160941. 
  9. ↑ "Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors". The Journal of Experimental Medicine 185 (9): 1693–1704. May 1997. doi:10.1084/jem.185.9.1693. PMID 9151906. 
  10. ↑ "Identification, cloning, and functional characterization of a murine lipoxin A4 receptor homologue gene". Journal of Immunology (Baltimore, Md.) 169 (6): 3363–3369. Sep 2002. doi:10.4049/jimmunol.169.6.3363. PMID 12218158. 
  11. ↑ "DHA- and EPA-derived resolvins, protectins, and maresins in airway inflammation". European Journal of Pharmacology 785: 144–155. Aug 2016. doi:10.1016/j.ejphar.2015.11.001. PMID 26546247. 
  12. ↑ "Basophils infiltrate human gastric mucosa at sites of Helicobacter pylori infection, and exhibit chemotaxis in response to H. pylori-derived peptide Hp(2-20)". Journal of Immunology (Baltimore, Md.) 172 (12): 7734–7743. Jun 2004. doi:10.4049/jimmunol.172.12.7734. PMID 15187157. 
  13. ↑ "House dust mite allergen activates human eosinophils via formyl peptide receptor and formyl peptide receptor-like 1". European Journal of Immunology 37 (7): 1966–1977. Jul 2007. doi:10.1002/eji.200636936. PMID 17559171. 
  14. ↑ "Adrenergic modulation of migration, CD11b and CD18 expression, ROS and interleukin-8 production by human polymorphonuclear leukocytes". Inflammation Research 64 (2): 127–135. Feb 2015. doi:10.1007/s00011-014-0791-8. PMID 25561369. 
  15. ↑ 15.0 15.1 "Pleurocidin, a novel antimicrobial peptide, induces human mast cell activation through the FPRL1 receptor". Mucosal Immunology 7 (1): 177–187. Jan 2014. doi:10.1038/mi.2013.37. PMID 23839065. 
  16. ↑ "The formylpeptide chemoattractant receptor copurifies with a GTP-binding protein containing a distinct 40-kDa pertussis toxin substrate". The Journal of Biological Chemistry 263 (10): 4969–4976. Apr 1988. doi:10.1016/S0021-9258(18)68882-9. PMID 2832415. 
  17. ↑ "Synthesis and use of a novel N-formyl peptide derivative to isolate a human N-formyl peptide receptor cDNA". Biochemical and Biophysical Research Communications 168 (3): 1103–1109. May 1990. doi:10.1016/0006-291x(90)91143-g. PMID 2161213. Bibcode: 1990BBRC..168.1103B. 
  18. ↑ 18.0 18.1 "The human N-formylpeptide receptor. Characterization of two cDNA isolates and evidence for a new subfamily of G-protein-coupled receptors". Biochemistry 29 (50): 11123–11133. Dec 1990. doi:10.1021/bi00502a016. PMID 2176894. 
  19. ↑ "The formyl peptide chemoattractant receptor is encoded by a 2 kilobase messenger RNA. Expression in Xenopus oocytes". FEBS Letters 261 (2): 353–357. Feb 1990. doi:10.1016/0014-5793(90)80590-f. PMID 1690150. Bibcode: 1990FEBSL.261..353M. 
  20. ↑ "Functional reconstitution of fMet-Leu-Phe receptor in Xenopus laevis oocytes". The Journal of Biological Chemistry 265 (11): 5964–5966. Apr 1990. doi:10.1016/S0021-9258(19)39276-2. PMID 2156834. 
  21. ↑ "Cloning of the gene coding for a human receptor for formyl peptides. Characterization of a promoter region and evidence for polymorphic expression". Biochemistry 31 (46): 11595–11599. Nov 1992. doi:10.1021/bi00161a044. PMID 1445895. 
  22. ↑ "Mapping of genes for the human C5a receptor (C5AR), human FMLP receptor (FPR), and two FMLP receptor homologue orphan receptors (FPRH1, FPRH2) to chromosome 19". Genomics 13 (2): 437–440. Jun 1992. doi:10.1016/0888-7543(92)90265-t. PMID 1612600. 
  23. ↑ 23.0 23.1 "A structural homologue of the N-formyl peptide receptor. Characterization and chromosome mapping of a peptide chemoattractant receptor family". The Journal of Biological Chemistry 267 (11): 7637–7643. Apr 1992. doi:10.1016/S0021-9258(18)42563-X. PMID 1373134. 
  24. ↑ "Isolation of a cDNA that encodes a novel granulocyte N-formyl peptide receptor". Biochemical and Biophysical Research Communications 184 (2): 582–589. Apr 1992. doi:10.1016/0006-291x(92)90629-y. PMID 1374236. Bibcode: 1992BBRC..184..582Y. 
  25. ↑ "Anti-inflammatory role of the murine formyl-peptide receptor 2: ligand-specific effects on leukocyte responses and experimental inflammation". Journal of Immunology (Baltimore, Md.) 184 (5): 2611–2619. Mar 2010. doi:10.4049/jimmunol.0903526. PMID 20107188. 
  26. ↑ "Formylpeptide receptors are critical for rapid neutrophil mobilization in host defense against Listeria monocytogenes". Scientific Reports 2. 2012. doi:10.1038/srep00786. PMID 23139859. Bibcode: 2012NatSR...2..786L. 
  27. ↑ "Resolvin D1 binds human phagocytes with evidence for proresolving receptors". Proceedings of the National Academy of Sciences of the United States of America 107 (4): 1660–1665. Jan 2010. doi:10.1073/pnas.0907342107. PMID 20080636. Bibcode: 2010PNAS..107.1660K. 
  28. ↑ "Omega-3 fatty acid-derived mediators 17(R)-hydroxy docosahexaenoic acid, aspirin-triggered resolvin D1 and resolvin D2 prevent experimental colitis in mice". Journal of Immunology (Baltimore, Md.) 187 (4): 1957–1969. Aug 2011. doi:10.4049/jimmunol.1101305. PMID 21724996. 
  29. ↑ "Induction of functional lipoxin A4 receptors in HL-60 cells". Blood 81 (12): 3395–3403. Jun 1993. doi:10.1182/blood.V81.12.3395.3395. PMID 8389617. 
  30. ↑ "Identification of a human cDNA encoding a functional high affinity lipoxin A4 receptor". The Journal of Experimental Medicine 180 (1): 253–260. Jul 1994. doi:10.1084/jem.180.1.253. PMID 8006586. 
  31. ↑ "Selectivity of recombinant human leukotriene D(4), leukotriene B(4), and lipoxin A(4) receptors with aspirin-triggered 15-epi-LXA(4) and regulation of vascular and inflammatory responses". The American Journal of Pathology 158 (1): 3–9. Jan 2001. doi:10.1016/S0002-9440(10)63937-5. PMID 11141472. 
  32. ↑ "Cloning of a cDNA encoding a receptor related to the formyl peptide receptor of human neutrophils". Gene 118 (2): 303–304. Sep 1992. doi:10.1016/0378-1119(92)90208-7. PMID 1511907. 
  33. ↑ "The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution". Seminars in Immunology 27 (3): 200–215. Apr 2015. doi:10.1016/j.smim.2015.03.004. PMID 25857211. 
  34. ↑ "Lipoxin and aspirin-triggered lipoxins". TheScientificWorldJournal 10: 1048–1064. Jun 2010. doi:10.1100/tsw.2010.113. PMID 20526535. 
  35. ↑ "Proresolving lipid mediators and mechanisms in the resolution of acute inflammation". Immunity 40 (3): 315–327. Mar 2014. doi:10.1016/j.immuni.2014.02.009. PMID 24656045. 
  36. ↑ "The Role of Formylated Peptides and Formyl Peptide Receptor 1 in Governing Neutrophil Function during Acute Inflammation". The American Journal of Pathology 185 (5): 1172–1184. May 2015. doi:10.1016/j.ajpath.2015.01.020. PMID 25791526. 
  37. ↑ "The N-formyl peptide receptors: much more than chemoattractant receptors. Relevance in health and disease". Frontiers in Immunology 16. 2025. doi:10.3389/fimmu.2025.1568629. PMID 40103822. 
  38. ↑ "Recent advances in the design and development of formyl peptide receptor 2 (FPR2/ALX) agonists as pro-resolving agents with diverse therapeutic potential". European Journal of Medicinal Chemistry 213. March 2021. doi:10.1016/j.ejmech.2021.113167. PMID 33486199. 

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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