C5aR

C5a receptor, also known as CD88, is a G protein-coupled receptor that binds the complement-derived inflammatory peptide C5a. In humans, the receptor is encoded by the C5AR1 gene and is expressed on a range of cell types, including neutrophils, monocytes, macrophages, dendritic cells, eosinophils, basophils, endothelial cells, and various epithelial cells. It plays a central role in mediating the proinflammatory effects of the complement system.

Upon binding C5a, C5aR1 activates heterotrimeric Gi proteins, leading to inhibition of adenylyl cyclase, mobilization of intracellular calcium through phospholipase C, and activation of MAP kinases. These signaling events drive chemotaxis, degranulation, reactive oxygen species production, phagocytosis, and release of proinflammatory cytokines and chemokines. Receptor desensitization and internalization occur via β-arrestin–dependent mechanisms. C5aR1 function is frequently considered alongside C5aR2 (also known as C5L2), a related receptor that can modulate or intersect signaling in a context-dependent manner.

Clinical and research significance: The C5a–C5aR1 axis is a major contributor to inflammatory pathology and has been implicated in conditions such as sepsis, acute lung injury, rheumatoid arthritis, systemic lupus erythematosus, and transplant rejection. Therapeutic strategies include antagonists designed to block C5aR1 signaling. Notable examples are peptide antagonists like PMX53 and clinically relevant agents such as avacopan (CCX168), an oral C5aR1 antagonist that has progressed in trials for ANCA-associated vasculitis. Ongoing research explores broader applications and safety in complement-mediated diseases.