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Functional roles for C5a receptors in sepsis

Nature Medicine volume 14, pages 551–557 (2008)Cite this article

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.

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Figure 1: Characterization of antibodies to C5a receptors.
Figure 2: Survival curves for mice after mid-grade CLP.
Figure 3: Survival curves for high-grade CLP under various conditions.
Figure 4: Build-up of HMGB1 in plasma during experimental sepsis.
Figure 5: Requirement of C5l2 for the release of HMGB1 in vitro.

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Acknowledgements

This work was supported by US National Institutes of Health grants GM-29507, GM-61656 and HL-31963 (to P.A.W.), AI-057839 (to J.K.) and HL-69511 (to C.G.) and Deutsche Forschungsgemeinschaft grants HU823/2-2 and HU823/2-3 (to M.H.-L.). We thank B. Schumann and S. Scott for secretarial assistance in preparation of the manuscript.

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Authors and Affiliations

  1. Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, 48109, Michigan, USA

    Daniel Rittirsch, Michael A Flierl, Brian A Nadeau, Danielle E Day, Firas S Zetoune, J Vidya Sarma & Peter A Ward

  2. Department of Traumatology, Hand-, Plastic- and Reconstructive Surgery, University Hospital Ulm, Steinhövelstrasse 9, Ulm, D-89075, Germany

    Markus Huber-Lang

  3. Immunology and Inflammation Department, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, 2010, New South Wales, Australia

    Charles R Mackay

  4. Pulmonary Division, Department of Pediatrics, Children's Hospital, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Norma P Gerard & Craig Gerard

  5. Department of Medicine, Harvard Medical School, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Norma P Gerard

  6. Centre de Recherche Hôpital Laval, Université Laval, 2725 chemin Ste Foy, Québec, G1V 4G5, Canada

    Katherine Cianflone

  7. Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center, 300 Longwood Avenue, Cincinnati, 45229, Ohio, USA

    Jörg Köhl

  8. Institute for Systemic Inflammation Research, University of Lübeck, Ratzeburger Allee 160, Lübeck, D-23538, Germany

    Jörg Köhl

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  1. Daniel Rittirsch
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Contributions

D.R. conducted all experiments and wrote the manuscript. M.A.F., B.A.N., D.E.D. and M.H.-L. contributed to the in vivo studies. C.R.M., F.S.Z. and N.P.G. made contributions to some of the in vitro experiments. K.C., J.K. and C.G. provided knockout mice and receptor antagonists. J.V.S. and P.A.W. supervised the project and edited the manuscript.

Corresponding author

Correspondence to Peter A Ward.

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Rittirsch, D., Flierl, M., Nadeau, B. et al. Functional roles for C5a receptors in sepsis. Nat Med 14, 551–557 (2008). https://doi.org/10.1038/nm1753

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