Functional roles for C5a receptors in sepsis.

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.

• Authors: Daniel Rittirsch, Michael A Flierl, Brian A Nadeau, Danielle E Day, Markus Huber-Lang, Charles R Mackay, Firas S Zetoune, Norma P Gerard, Katherine Cianflone, Jörg Köhl, Craig Gerard, J Vidya Sarma, Peter A Ward
• Journal: Nature medicine (Nat Med) Vol. 14 Issue 5 Pg. 551-7 (May 2008) ISSN: 1546-170X [Electronic] United States
• PMID: 18454156 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• C5ar2 protein, mouse
• Chemokines
• Complement C3
• Cytokines
• HMGB1 Protein
• Immunoglobulin G
• Receptor, Anaphylatoxin C5a
• Receptors, Chemokine

Topics

• Animals
• Blotting, Western
• Chemokines (blood)
• Complement C3 (genetics, immunology)
• Cytokines (blood)
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• HMGB1 Protein (blood)
• Immunoglobulin G (immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Receptor, Anaphylatoxin C5a (genetics, immunology)
• Receptors, Chemokine (genetics, immunology)
• Sepsis (immunology)
• Survival Analysis