C5AR2 explained

Complement component 5a receptor 2 is a protein of the complement system that in humans is encoded by the C5AR2 gene.[1] [2] It is highly expressed in the blood and spleen,[3] predominantly by myeloid cells.[4] [5]

Function

The anaphylatoxins C3a and C5a are fragments of C3 and C5 generated via proteolytic cleavage by C3 convertases and C5 convertases during the complement cascade. They are pro-inflammatory mediators which bind to the anaphylatoxin receptors, C3aR, C5aR1 and C5aR2. The anaphylatoxin receptors are a family of three proteins which beloing to the G protein-coupled receptor superfamily. C3aR and C5aR1 bind C3a and C5a, respectively, which mediate a broad range of effects in host defense, including chemoattraction, vasodilation and immune cell activation.[6] C5aR2 binds C5a, but lacks GPCR activity,[7] and its function is less well understood.

C5aR2 was initially thought be a decoy receptor, acting as a sink for C5a to negatively regulate C5aR1 function. However, more recent research has uncovered independent roles for C5aR2, including modulation of the innate immune response in myeloid cells,[8] [9] translocation of C5a to drive transendothelial migration of neutrophils,[10] β-arrestin recruitment and modulation of ERK signalling[11] [12] and modulation of lipid metabolism in obesity through C3a-desArg binding.[13] C5aR2 has been implicated in a broad range of inflammatory and infectious diseases.[14] [15]

Notes and References

  1. Ohno M, Hirata T, Enomoto M, Araki T, Ishimaru H, Takahashi TA . A putative chemoattractant receptor, C5L2, is expressed in granulocyte and immature dendritic cells, but not in mature dendritic cells . Molecular Immunology . 37 . 8 . 407–412 . June 2000 . 11090875 . 10.1016/S0161-5890(00)00067-5 .
  2. Web site: HGNC:4527 . 2019-08-30.
  3. Zhu Y, Wang X, Xu Y, Chen L, Ding P, Chen J, Hu W . An Integrated Analysis of C5AR2 Related to Malignant Properties and Immune Infiltration of Breast Cancer . Frontiers in Oncology . 11 . 736725 . 2021-09-14 . 34595119 . 8476960 . 10.3389/fonc.2021.736725 . free .
  4. Bamberg CE, Mackay CR, Lee H, Zahra D, Jackson J, Lim YS, Whitfeld PL, Craig S, Corsini E, Lu B, Gerard C, Gerard NP . The C5a receptor (C5aR) C5L2 is a modulator of C5aR-mediated signal transduction . The Journal of Biological Chemistry . 285 . 10 . 7633–7644 . March 2010 . 20044484 . 2844210 . 10.1074/jbc.M109.092106 . free .
  5. Karsten CM, Wiese AV, Mey F, Figge J, Woodruff TM, Reuter T, Scurtu O, Kordowski A, Almeida LN, Briukhovetska D, Quell KM, Sun J, Ender F, Schmudde I, Vollbrandt T, Laumonnier Y, Köhl J . Monitoring C5aR2 Expression Using a Floxed tdTomato-C5aR2 Knock-In Mouse . Journal of Immunology . 199 . 9 . 3234–3248 . November 2017 . 28864475 . 10.4049/jimmunol.1700710 .
  6. Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Köhl J . The role of the anaphylatoxins in health and disease . Molecular Immunology . 46 . 14 . 2753–2766 . September 2009 . 19477527 . 2725201 . 10.1016/j.molimm.2009.04.027 . 12th European Meeting on Complement in Human Disease .
  7. Scola AM, Johswich KO, Morgan BP, Klos A, Monk PN . The human complement fragment receptor, C5L2, is a recycling decoy receptor . Molecular Immunology . 46 . 6 . 1149–1162 . March 2009 . 19100624 . 2697321 . 10.1016/j.molimm.2008.11.001 .
  8. Li XX, Clark RJ, Woodruff TM . C5aR2 Activation Broadly Modulates the Signaling and Function of Primary Human Macrophages . Journal of Immunology . 205 . 4 . 1102–1112 . August 2020 . 32611725 . 10.4049/jimmunol.2000407 .
  9. Wright O, Harris A, Nguyen VD, Zhou Y, Durand M, Jayyaratnam A, Gormley D, O'Neill LA, Triantafilou K, Nichols EM, Booty LM . C5aR2 Regulates STING-Mediated Interferon Beta Production in Human Macrophages . Cells . 12 . 23 . 2707 . November 2023 . 38067135 . 10706378 . 10.3390/cells12232707 . free .
  10. Miyabe Y, Miyabe C, Mani V, Mempel TR, Luster AD . Atypical complement receptor C5aR2 transports C5a to initiate neutrophil adhesion and inflammation . Science Immunology . 4 . 35 . May 2019 . 31076525 . 10.1126/sciimmunol.aav5951 .
  11. Croker DE, Monk PN, Halai R, Kaeslin G, Schofield Z, Wu MC, Clark RJ, Blaskovich MA, Morikis D, Floudas CA, Cooper MA, Woodruff TM . Discovery of functionally selective C5aR2 ligands: novel modulators of C5a signalling . Immunology and Cell Biology . 94 . 8 . 787–795 . September 2016 . 27108698 . 10.1038/icb.2016.43 .
  12. Croker DE, Halai R, Kaeslin G, Wende E, Fehlhaber B, Klos A, Monk PN, Cooper MA . C5a2 can modulate ERK1/2 signaling in macrophages via heteromer formation with C5a1 and β-arrestin recruitment . Immunology and Cell Biology . 92 . 7 . 631–639 . August 2014 . 24777312 . 10.1038/icb.2014.32 . 24704330 .
  13. Fisette . Alexandre . Cianflone . Katherine . 2010-06-01 . The ASP and C5L2 pathway: another bridge between inflammation and metabolic homeostasis . Clinical Lipidology . en . 5 . 3 . 367–377 . 10.2217/clp.10.21 . 85816536 . 1758-4299.
  14. Li R, Coulthard LG, Wu MC, Taylor SM, Woodruff TM . C5L2: a controversial receptor of complement anaphylatoxin, C5a . FASEB Journal . 27 . 3 . 855–864 . March 2013 . 23239822 . 10.1096/fj.12-220509 . free .
  15. Li XX, Lee JD, Kemper C, Woodruff TM . The Complement Receptor C5aR2: A Powerful Modulator of Innate and Adaptive Immunity . Journal of Immunology . 202 . 12 . 3339–3348 . June 2019 . 31160390 . 10.4049/jimmunol.1900371 .

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