Cutting edge: Targeted disruption of the C3a receptor gene demonstrates a novel protective anti-inflammatory role for C3a in endotoxin-shock

The complement anaphylatoxin C3a, on binding the C3aR, mediates numerous pr oinflammatory activities. In addition, recent in vitro studies with C3a hav e implicated C3aR as a possible anti-inflammatory receptor. Because of its possible dual role in modulating the inflammatory response, it is uncertain whether C3aR contributes to the pathogenesis of endotoxin shock. Here, the targeted-disruption of the C3aR in mice is reported, These mice exhibit an enhanced lethality to endotoxin shock with a pronounced gene dosage effect , In addition, the plasma concentration of LL-1 beta was significantly elev ated in the C3aR(-/-) mice compared with their littermates following LPS ch allenge. These findings demonstrate an important protective role for the C3 aR in endotoxin shock and indicate that, in addition to its traditionally a ccepted functions in mediating inflammation, the C3aR also acts in vivo as an anti-inflammatory receptor by attenuating LPS-induced proinflammatory cy tokine production.