Anti-inflammatory signaling through G protein-coupled receptors


G protein-coupled receptors (GPCRs) play important roles in human physiology. GPCRs are involved in immunoregulation including regulation of the inflammatory response. Chemotaxis of phagocytes and lymphocytes is mediated to a great extent by the GPCRs for chemoattractants including myriads of chemokines. Accumulation and activation of phagocytes at the site of inflammation contribute to local inflammatory response. A handful of GPCRs have been found to transduce anti-inflammatory signals that promote resolution of inflammation. These GPCRs interact with selected metabolites of arachdonic acid, such as lipoxins, and of omega-3 essential fatty acids, such as resolvins and protectins. Despite mounting evidence for the in vivo functions of these anti-inflammatory and pro-resolving ligands paired with their respective GPCRs, the underlying signaling mechanisms have not been fully delineated. The present review summarizes what we have learned about these GPCRs, their structures and signaling pathways and the prospect of targeting these receptors for novel anti-inflammatory therapies.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Signaling pathways of FPR2 activated by proinflammatory ligands.
Fig. 2: Anti-inflammatory and pro-resolving signaling through dimerized FPR2.
Fig. 3: Energy landscape changes induced by ATL binding to FPR2.
Fig. 4: Overall structure of the FPR2-LXA4 complex.
Fig. 5: Mode of FPR2 binding to the LXA4 ligand.


  1. 1.

    Blake DR, Allen R. Inflammation: basic principles and clinical correlates. Ann Rheum Dis. 1988;47:792.

    PubMed Central  Google Scholar 

  2. 2.

    Serhan CN, Levy BD. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest. 2018;128:2657–69.

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Bacchi S, Palumbo P, Sponta A, Coppolino MF. Clinical pharmacology of non-steroidal anti-inflammatory drugs: a review. Antiinflamm Antiallergy Agents Med Chem. 2012;11:52–64.

    CAS  PubMed  Google Scholar 

  4. 4.

    Perez DM. From plants to man: the GPCR “tree of life”. Mol Pharmacol. 2005;67:1383–4.

    CAS  PubMed  Google Scholar 

  5. 5.

    Ley K, Hoffman HM, Kubes P, Cassatella MA, Zychlinsky A, Hedrick CC, et al. Neutrophils: new insights and open questions. Sci Immunol. 2018;3:eaat4579.

    PubMed  Google Scholar 

  6. 6.

    Ye RD, Boulay F, Wang JM, Dahlgren C, Gerard C, Parmentier M, et al. International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family. Pharmacol Rev. 2009;61:119–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011;31:986–1000.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Ollivier V, Parry GC, Cobb RR, de Prost D, Mackman N. Elevated cyclic AMP inhibits NF-kappaB-mediated transcription in human monocytic cells and endothelial cells. J Biol Chem. 1996;271:20828–35.

    CAS  PubMed  Google Scholar 

  9. 9.

    Fan J, Ye RD, Malik AB. Transcriptional mechanisms of acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2001;281:L1037–50.

    CAS  PubMed  Google Scholar 

  10. 10.

    Grabiner BC, Blonska M, Lin PC, You Y, Wang D, Sun J, et al. CARMA3 deficiency abrogates G protein-coupled receptor-induced NF-{kappa}B activation. Genes Dev. 2007;21:984–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Ye RD. Regulation of nuclear factor kappaB activation by G-protein-coupled receptors. J Leukoc Biol. 2001;70:839–48.

    CAS  PubMed  Google Scholar 

  12. 12.

    Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510:92–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Dalli J, Zhu M, Vlasenko NA, Deng B, Haeggstrom JZ, Petasis NA, et al. The novel 13S,14S-epoxy-maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H), and shifts macrophage phenotype. FASEB J. 2013;27:2573–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765.

    CAS  PubMed  Google Scholar 

  15. 15.

    Fiore S, Maddox JF, Perez HD, Serhan CN. Identification of a human cDNA encoding a functional high affinity lipoxin A4 receptor. J Exp Med. 1994;180:253–60.

    CAS  PubMed  Google Scholar 

  16. 16.

    Chiang N, Fierro IM, Gronert K, Serhan CN. Activation of lipoxin A(4) receptors by aspirin-triggered lipoxins and select peptides evokes ligand-specific responses in inflammation. J Exp Med. 2000;191:1197–208.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Chiang N, Serhan CN. Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors. Mol Asp Med. 2017;58:114–29.

    CAS  Google Scholar 

  18. 18.

    Chiang N, Dalli J, Colas RA, Serhan CN. Identification of resolvin D2 receptor mediating resolution of infections and organ protection. J Exp Med. 2015;212:1203–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Bang S, Xie YK, Zhang ZJ, Wang Z, Xu ZZ, Ji RR. GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain. J Clin Invest. 2018;128:3568–82.

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Chiang N, Libreros S, Norris PC, de la Rosa X, Serhan CN. Maresin 1 activates LGR6 receptor promoting phagocyte immunoresolvent functions. J Clin Invest. 2019;129:5294–311.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Serhan CN, Hamberg M, Samuelsson B. Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes. Proc Natl Acad Sci USA. 1984;81:5335–9.

    CAS  PubMed  Google Scholar 

  22. 22.

    Colgan SP, Serhan CN, Parkos CA, Delp-Archer C, Madara JL. Lipoxin A4 modulates transmigration of human neutrophils across intestinal epithelial monolayers. J Clin Invest. 1993;92:75–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Claria J, Serhan CN. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell–leukocyte interactions. Proc Natl Acad Sci USA. 1995;92:9475–9.

    CAS  PubMed  Google Scholar 

  24. 24.

    @Serhan CN. Lipoxins and novel aspirin-triggered 15-epi-lipoxins (ATL): a jungle of cell–cell interactions or a therapeutic opportunity? Prostaglandins. 1997;53:107–37.

    CAS  PubMed  Google Scholar 

  25. 25.

    Fiore S, Ryeom SW, Weller PF, Serhan CN. Lipoxin recognition sites. Specific binding of labeled lipoxin A4 with human neutrophils. J Biol Chem. 1992;267:16168–76.

    CAS  PubMed  Google Scholar 

  26. 26.

    Maddox JF, Hachicha M, Takano T, Petasis NA, Fokin VV, Serhan CN. Lipoxin A4 stable analogs are potent mimetics that stimulate human monocytes and THP-1 cells via a G-protein-linked lipoxin A4 receptor. J Biol Chem. 1997;272:6972–8.

    CAS  PubMed  Google Scholar 

  27. 27.

    Maderna P, Cottell DC, Toivonen T, Dufton N, Dalli J, Perretti M, et al. FPR2/ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis. FASEB J. 2010;24:4240–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Forsman H, Dahlgren C. Lipoxin A(4) metabolites/analogues from two commercial sources have no effects on TNF-alpha-mediated priming or activation through the neutrophil formyl peptide receptors. Scand J Immunol. 2009;70:396–402.

    CAS  PubMed  Google Scholar 

  29. 29.

    Forsman H, Onnheim K, Andreasson E, Dahlgren C. What formyl peptide receptors, if any, are triggered by compound 43 and lipoxin A4? Scand J Immunol. 2011;74:227–34.

    CAS  PubMed  Google Scholar 

  30. 30.

    Hanson J, Ferreiros N, Pirotte B, Geisslinger G, Offermanns S. Heterologously expressed formyl peptide receptor 2 (FPR2/ALX) does not respond to lipoxin A(4). Biochem Pharm. 2013;85:1795–802.

    CAS  PubMed  Google Scholar 

  31. 31.

    Cooray SN, Gobbetti T, Montero-Melendez T, McArthur S, Thompson D, Clark AJ, et al. Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses. Proc Natl Acad Sci USA. 2013;110:18232–7.

    CAS  PubMed  Google Scholar 

  32. 32.

    Su SB, Gong W, Gao JL, Shen W, Murphy PM, Oppenheim JJ, et al. A seven-transmembrane, G protein-coupled receptor, FPRL1, mediates the chemotactic activity of serum amyloid A for human phagocytic cells. J Exp Med. 1999;189:395–402.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    He R, Sang H, Ye RD. Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1/LXA4R. Blood. 2003;101:1572–81.

    CAS  PubMed  Google Scholar 

  34. 34.

    Ge Y, Zhang S, Wang J, Xia F, Wan JB, Lu J, et al. Dual modulation of formyl peptide receptor 2 by aspirin-triggered lipoxin contributes to its anti-inflammatory activity. FASEBJ. 2020;34:6920–33.

    CAS  Google Scholar 

  35. 35.

    Hilger D, Masureel M, Kobilka BK. Structure and dynamics of GPCR signaling complexes. Nat Struct Mol Biol. 2018;25:4–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Mills JS, Miettinen HM, Cummings D, Jesaitis AJ. Characterization of the binding site on the formyl peptide receptor using three receptor mutants and analogs of Met-Leu-Phe and Met-Met-Trp-Leu-Leu. J Biol Chem. 2000;275:39012–7.

    CAS  PubMed  Google Scholar 

  37. 37.

    Quehenberger O, Prossnitz ER, Cavanagh SL, Cochrane CG, Ye RD. Multiple domains of the N-formyl peptide receptor are required for high-affinity ligand binding. Construction and analysis of chimeric N-formyl peptide receptors. J Biol Chem. 1993;268:18167–75.

    CAS  PubMed  Google Scholar 

  38. 38.

    Quehenberger O, Pan ZK, Prossnitz ER, Cavanagh SL, Cochrane CG, Ye RD. Identification of an N-formyl peptide receptor ligand binding domain by a gain-of-function approach. Biochem Biophys Res Commun. 1997;238:377–81.

    CAS  PubMed  Google Scholar 

  39. 39.

    Mills JS, Miettinen HM, Barnidge D, Vlases MJ, Wimer-Mackin S, Dratz EA, et al. Identification of a ligand binding site in the human neutrophil formyl peptide receptor using a site-specific fluorescent photoaffinity label and mass spectrometry. J Biol Chem. 1998;273:10428–35.

    CAS  PubMed  Google Scholar 

  40. 40.

    He HQ, Troksa EL, Caltabiano G, Pardo L, Ye RD. Structural determinants for the interaction of formyl peptide receptor 2 with peptide ligands. J Biol Chem. 2014;289:2295–306.

    CAS  PubMed  Google Scholar 

  41. 41.

    Zhuang Y, Liu H, Edward Zhou X, Kumar Verma R, de Waal PW, Jang W, et al. Structure of formylpeptide receptor 2-Gi complex reveals insights into ligand recognition and signaling. Nat Commun. 2020;11:885.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Chen T, Xiong M, Zong X, Ge Y, Zhang H, Wang M, et al. Structural basis of ligand binding modes at the human formyl peptide receptor 2. Nat Commun. 2020;11:1208.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    He M, Cheng N, Gao WW, Zhang M, Zhang YY, Ye RD, et al. Characterization of Quin-C1 for its anti-inflammatory property in a mouse model of bleomycin-induced lung injury. Acta Pharmacol Sin. 2011;32:601–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Nanamori M, Cheng X, Mei J, Sang H, Xuan Y, Zhou C, et al. A novel nonpeptide ligand for formyl peptide receptor-like 1. Mol Pharmacol. 2004;66:1213–22.

    CAS  PubMed  Google Scholar 

  45. 45.

    Kao W, Gu R, Jia Y, Wei X, Fan H, Harris J, et al. A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis. Br J Pharmacol. 2014;171:4087–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Burli RW, Xu H, Zou X, Muller K, Golden J, Frohn M, et al. Potent hFPRL1 (ALXR) agonists as potential anti-inflammatory agents. Bioorg Med Chem Lett. 2006;16:3713–8.

    PubMed  Google Scholar 

  47. 47.

    Qin CX, May LT, Li R, Cao N, Rosli S, Deo M, et al. Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice. Nat Commun. 2017;8:14232.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Krishnamoorthy S, Recchiuti A, Chiang N, Yacoubian S, Lee CH, Yang R, et al. Resolvin D1 binds human phagocytes with evidence for proresolving receptors. Proc Natl Acad Sci USA. 2010;107:1660–5.

    CAS  PubMed  Google Scholar 

  49. 49.

    Arnardottir HH, Dalli J, Norling LV, Colas RA, Perretti M, Serhan CN. Resolvin D3 is dysregulated in arthritis and reduces arthritic inflammation. J Immunol. 2016;197:2362–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Chiang N, Fredman G, Backhed F, Oh SF, Vickery T, Schmidt BA, et al. Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature. 2012;484:524–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Dalli J, Winkler JW, Colas RA, Arnardottir H, Cheng CY, Chiang N, et al. Resolvin D3 and aspirin-triggered resolvin D3 are potent immunoresolvents. Chem Biol. 2013;20:188–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Arita M, Bianchini F, Aliberti J, Sher A, Chiang N, Hong S, et al. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J Exp Med. 2005;201:713–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Arita M, Ohira T, Sun YP, Elangovan S, Chiang N, Serhan CN. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J Immunol. 2007;178:3912–7.

    CAS  PubMed  Google Scholar 

  54. 54.

    Oh SF, Pillai PS, Recchiuti A, Yang R, Serhan CN. Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation. J Clin Invest. 2011;121:569–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Laskowski RA, Swindells MB. LigPlot+: multiple ligand–protein interaction diagrams for drug discovery. J Chem Inf Model. 2011;51:2778–86.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


This work was supported in part by grants from the Fundo para o Desenvolvimento das Ciências e da Tecnologia (FDCT 072/2015/A2) and from the University of Macau (MYRG2016-00246-ICMS-QRCM). YJG and RDY were supported by the President Fund of the Chinese University of Hong Kong, Shenzhen. QWL was supported by the Ganghong Young Scholar Development Fund.

Author information



Corresponding author

Correspondence to Richard D. Ye.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ge, Yj., Liao, Qw., Xu, Yc. et al. Anti-inflammatory signaling through G protein-coupled receptors. Acta Pharmacol Sin 41, 1531–1538 (2020).

Download citation