C5AR1

C5a receptor 1 (C5aR1), also known as CD88, is a G protein–coupled receptor that binds the anaphylatoxin C5a, a potent inflammatory mediator generated during activation of the complement system. In humans, it is encoded by the C5AR1 gene. C5aR1 recognizes C5a with high affinity and, upon activation, drives a range of inflammatory responses.

C5aR1 is a seven-transmembrane GPCR that primarily couples to the Gαi family of G proteins. Receptor activation leads to inhibition of intracellular cAMP production and triggers downstream signaling pathways, including MAPK/ERK and PI3K-Akt, as well as β-arrestin–dependent mechanisms. These signaling events promote leukocyte chemotaxis and recruitment, priming and degranulation of neutrophils, production of reactive oxygen species, release of proinflammatory cytokines, and upregulation of endothelial adhesion molecules. The receptor can thus amplify inflammatory responses at sites of infection or tissue injury.

Expression of C5aR1 is highest on myeloid cells such as neutrophils, monocytes, macrophages, and dendritic cells, but it is also found on eosinophils, basophils, mast cells, endothelial cells, and some neurons and glial cells in certain contexts. Regulation of C5aR1 signaling is complemented by C5a receptor 2 (C5aR2), which can modulate C5aR1 activity.

Clinically, C5aR1 is a target for anti-inflammatory therapies. Antagonists and antibodies aim to dampen excessive inflammation in conditions such as vasculitis, autoimmune diseases, sepsis, and ischemia-reperfusion injury. Avacopan (CCX168) is a notable C5aR1 antagonist that has been approved for certain inflammatory diseases, reflecting the receptor’s relevance as a therapeutic target. Blocking C5aR1 can reduce tissue injury but may carry risks related to impaired host defense against infection.