Functional roles for C5a receptors in sepsis

The function of the C5a receptors, C5ar ( encoded by C5ar) and C512 ( encoded by Gpr77), especially of C512, which was originally termed a 'default receptor', remains a controversial topic. Here we investigated the role of each receptor in the setting of cecal ligation and puncture-induced sepsis by using antibody-induced blockade of C5a receptors and knockout mice. In 'mid-grade' sepsis ( 30-40% survival), blockade or absence of either C5ar or C512 greatly improved survival and attenuated the buildup of proinflammatory mediators in plasma. In vivo appearance or in vitro release of high mobility group box 1 protein ( HMGB1) required C512 but not C5ar. In 'high-grade' sepsis ( 100% lethality), the only protective condition was the combined blockade of C512 and C5ar. These data suggest that C5ar and C512 contribute synergistically to the harmful consequences in sepsis and that C512 is required for the release of HMGB1. Thus, contrary to earlier speculation, C512 is a functional receptor rather than merely a default receptor.