The C5a receptor is a G protein-coupled receptor for C5a. It functions as a complement receptor.Rittirsch et al. (2008) used mice lacking C5ar or C5l2 (GPR77) or antibody-induced blockade of C5ar and C5l2 to investigate the roles of C5a receptors in sepsis induced by cecal ligation and puncture. They observed increased survival and attenuation of plasma proinflammatory mediator production in mid-grade sepsis when either receptor was blocked or absent. Expression of Hmgb1 , a key late mediator in sepsis, was dependent on C5l2, but not C5ar. In high-grade sepsis, only combined blockade of both C5ar and C5l2 afforded protection. Rittirsch et al. (2008) proposed that C5AR and C5L2 contribute synergistically to the harmful consequences in sepsis and that C5L2 is required for HMGB1 release.