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), andFPR3. The latter nomenclature is recommended by the International Union of Basic and Clinical Pharmacology[8] 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.[8]
The humanFPR2 gene encodes the 351 amino acid receptor, FPR2, within an intronlessopen reading frame. It forms a cluster withFPR1 andFPR3 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-coupledC5a 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.[9] The FPR1, FPR2, and FPR3paralogs, based onphylogenetic 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.[10]
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 (orfpr2),Fpr-rs1 (orLXA4R),Fpr-rs4,Fpr-rs7,Fpr-rs7,Fpr-rs6, andFpr-rs3; this locus also containsPseudogenesψFpr-rs2 andψFpr-rs3 (orψFpr-rs5) which lie just afterFpr-rs2 andFpr-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.[11]Fpr2 andmFpr-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;[12][13][14]
Early studies indicated that these peptides act through areceptor-mediated mechanism. To investigate this, researchers used the human leukocyte cell lineHL-60, which consists ofpromyelocytes that do not respond to FMLP. Upon differentiation intogranulocytes, which do respond, the cells were used to partially purify[20] andclone a gene. When this gene was transfected into FMLP-unresponsive cells, it conferred responsiveness to FMLP and other N-formyl oligopeptides.[21][22][23][24][25]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.[26][27][28] These three receptors were initially named inconsistently but are now designatedformyl peptide receptor 1 (FPR1), formyl peptide receptor 2 (FPR2; this gene), andformyl 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.[8] A major function of FPR2 is to bind certainspecialized pro-resolving mediators (SPMs)—includinglipoxin (Lx)A4, AT-LxA4 (arachidonic acid metabolites), andresolvin D1 (RvD1), RvD2, and AT-RvD1 (derived fromdocosahexaenoic 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.
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 theFpr2 andFpr3 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 intraperatoneal injection of arthritis-inducing serum.[29] SinceFpr2 gene knockout mice exhibit a faulty innate immune response to intravenouslisteria monocytogenes injection,[30] these results suggest that the human FPR2 receptor and mouse Fpr3 receptor have equivalent functions in dampening at least certain inflammatory response.
FPR2, also known as the LXA4 receptor or ALX/FPR2, was initially identified as a high-affinity receptor for thearachidonic acid metabolitelipoxin A4 (LXA4). It was later found to also bind the related metabolites aspirin-triggered lipoxin A4 (ATL, or 15-epi-LXA4), and thedocosahexaenoic acid derivativeresolvin D1 (RvD1). These three lipid mediators act to inhibit and resolve inflammation.[31][32][33][34][35]
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.[22][27][36]
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.[37] Nevertheless, FPR2 is best known for mediating the anti-inflammatory and pro-resolving actions of lipoxins and resolvins.[38][39]
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);
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