Complement peptide receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Complement peptide receptors [23]) are activated by the endogenous ~75 amino-acid anaphylatoxin polypeptides C3a (C3, P01024) and C5a (C5, P01031), generated upon stimulation of the complement cascade. C3a and C5a exert their functions through binding to their receptors (C3aR and C5aR), causing cell activation and triggering cellular degranulation that contributes to the local inflammation.

SB290157 has also been reported to have agonist properties at the C3a receptor [27,29]. The chemoattractant receptor C5a₂ (also known as GPR77, C5L2) binds C5a and has putative roles in either opposing or promoting inflammatory responses [8,15-16,28,33]. Binding to this site may be displaced with the rank order C5a des-Arg (C5)> C5a (C5, P01031) [8,32] while there is controversy over the ability of C3a (C3, P01024) and C3a des Arg (C3, P01024) to compete [17,20-21,32]. C5a₂ appears to lack G protein signalling and has been termed a decoy receptor [37]. However, C5a₂ does recruit β-arrestin after ligand binding, which might provide a signaling pathway for this receptor [4,42], and forms heteromers with C5a₁. C5a, but not C5a-des Arg, induces upregulation of heteromer formation between complement C5a receptors C5a₁ and C5a₂ [11]. There are also reports of pro-inflammatory activity of C5a₂, mediated by HMGB1, likely through AKT and MAPK signalling pathways (reviewed in [25,47]). In T cells it has shown that C5a₁ and C5a₂ act in opposition to each other and that altering the equilibrium between the two receptors, by differential expression or production of C5a-des Arg (which favours C5a₂), can affect the final cellular response [3]. Recently in human macrophages, C5a₂ was observed to modulate multiple complement and chemokine receptor-mediated signalling and pattern recognition-induced cytokine responses, independent of C5a₁ [26]. In addition, C5a₂ is reported to act as a C5a transporter on endothelial cells, and is required for the transport of C5a into the vessel lumen and the subsequent neutrophil arrest in arthritis [30].

* Key recommended reading is highlighted with an asterisk

* Arbore G, Kemper C. (2016) A novel "complement-metabolism-inflammasome axis" as a key regulator of immune cell effector function. Eur. J. Immunol., 46 (7): 1563-73. [PMID:27184294]

Coulthard LG, Hawksworth OA, Conroy J, Lee JD, Woodruff TM. (2018) Complement C3a receptor modulates embryonic neural progenitor cell proliferation and cognitive performance. Mol. Immunol., 101: 176-181. [PMID:30449309]

* Coulthard LG, Woodruff TM. (2015) Is the complement activation product C3a a proinflammatory molecule? Re-evaluating the evidence and the myth. J. Immunol., 194 (8): 3542-8. [PMID:25848071]

* Klos A, Wende E, Wareham KJ, Monk PN. (2013) International Union of Pharmacology. LXXXVII. Complement peptide C5a, C4a, and C3a receptors. Pharmacol. Rev., 65 (1): 500-43. [PMID:23383423]

Laumonnier Y, Karsten CM, Köhl J. (2017) Novel insights into the expression pattern of anaphylatoxin receptors in mice and men. Mol. Immunol., 89: 44-58. [PMID:28600003]

Li R, Coulthard LG, Wu MC, Taylor SM, Woodruff TM. (2013) C5L2: a controversial receptor of complement anaphylatoxin, C5a. FASEB J., 27 (3): 855-64. [PMID:23239822]

* Li XX, Lee JD, Kemper C, Woodruff TM. (2019) The Complement Receptor C5aR2: A Powerful Modulator of Innate and Adaptive Immunity. J Immunol, 202 (12): 3339-3348. [PMID:31160390]

Manthey HD, Woodruff TM, Taylor SM, Monk PN. (2009) Complement component 5a (C5a). Int. J. Biochem. Cell Biol., 41 (11): 2114-7. [PMID:19464229]

Monk PN, Scola AM, Madala P, Fairlie DP. (2007) Function, structure and therapeutic potential of complement C5a receptors. Br. J. Pharmacol., 152 (4): 429-48. [PMID:17603557]

* Pandey S, Maharana J, Li XX, Woodruff TM, Shukla AK. (2020) Emerging Insights into the Structure and Function of Complement C5a Receptors. Trends Biochem Sci, 45 (8): 693-705. [PMID:32402749]

Reichhardt MP, Meri S. (2018) Intracellular complement activation-An alarm raising mechanism?. Semin. Immunol., 38: 54-62. [PMID:29631809]

Sacks SH. (2010) Complement fragments C3a and C5a: the salt and pepper of the immune response. Eur. J. Immunol., 40 (3): 668-70. [PMID:20186746]

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Subcommittee members: Trent M. Woodruff (Chairperson) School of Biomedical Sciences The University of Queensland BNE, QUEENSLAND 4072 Australia Peter Monk Department of Infection and Immunity Sheffield University Medical School Beech Hill Road Sheffield S10 2RX, UK

Other contributors: Antonia Cianciulli Department of Pharmaco-Biology University of Bari Italy Liam Coulthard School of Biomedical Sciences The University of Queensland BNE, QUEENSLAND 4072 Owen Hawksworth School of Biomedical Sciences The University of Queensland BNE, QUEENSLAND 4072 Australia John D. Lee School of Biomedical Sciences The University of Queensland BNE, QUEENSLAND 4072 Australia Xiang X. Li The School of Biomedical Sciences The University of Queensland BNE, QUEENSLAND 4072 Australia Vincenzo Mitolo Department of Pharmaco-Biology University of Bari Italy Maria A. Panaro Department of Pharmaco-Biology University of Bari Italy