Abstract

The function of the C5a receptors, C5ar (encoded by C5ar) and C5l2 (encoded by Gpr77), especially of C5l2, 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 C5l2 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 C5l2 but not C5ar. In 'high-grade' sepsis (100% lethality), the only protective condition was the combined blockade of C5l2 and C5ar. These data suggest that C5ar and C5l2 contribute synergistically to the harmful consequences in sepsis and that C5l2 is required for the release of HMGB1. Thus, contrary to earlier speculation, C5l2 is a functional receptor rather than merely a default receptor.

1. Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, Michigan 48109, USA.
2. Department of Traumatology, Hand-, Plastic- and Reconstructive Surgery, University Hospital Ulm, Steinhövelstrasse 9, D-89075 Ulm, Germany.
3. Immunology and Inflammation Department, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.
4. Pulmonary Division, Department of Pediatrics, Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
5. Department of Medicine, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
6. Centre de Recherche Hôpital Laval, Université Laval, 2725 chemin Ste Foy, Québec G1V 4G5, Canada.
7. Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center, 300 Longwood Avenue, Cincinnati, Ohio 45229, USA.
8. Institute for Systemic Inflammation Research, University of Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany.

Correspondence to: Peter A Ward¹ e-mail: pward@umich.edu

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