C5AR2

C5a receptor 2 (C5aR2), also known as C5L2, is a receptor for the complement component C5a. It is a member of the seven-transmembrane G protein-coupled receptor family, but its signaling profile differs from the classical C5a receptor (C5aR1, CD88). In humans, C5AR2 is encoded by the C5AR2 gene.

Unlike C5aR1, which robustly activates G protein–dependent pathways leading to chemotaxis and inflammatory mediator release, C5aR2 generally shows weak or context-dependent G protein coupling. It is thought to function as a decoy or scavenger receptor in some settings, helping to limit excessive C5a activity. There is also evidence that C5aR2 can signal through β-arrestin–dependent pathways and may influence MAPK signaling, with effects that vary by cell type and ligand form. Through these mechanisms, C5aR2 can modulate, enhance, or dampen C5aR1-driven responses.

Expression of C5aR2 has been detected on neutrophils, monocytes, macrophages, dendritic cells, endothelial cells, and some non-hematopoietic tissues. Its physiological roles include participation in the regulation of inflammation, leukocyte recruitment, vascular permeability, and cytokine production. In disease models, C5aR2 function appears context-dependent, contributing to both pro- and anti-inflammatory outcomes depending on the setting.

Therapeutically, understanding C5aR2 is important because it can influence inflammatory responses by modulating C5aR1 signaling or acting as a sink for C5a. As of now, no therapies target C5aR2 specifically. See also the complement system and C5a.