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Functional Roles for C5a Receptors in Sepsis
Author(s) -
Rittirsch Daniel,
Sarma J. Vidya,
Day Danielle E.,
Nadeau Brian A.,
Zetoune Firas S.,
Chen Anthony J.,
HuberLang Markus S.,
Flierl Michael A.,
Ward Peter A.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.48.10
Subject(s) - c5a receptor , sepsis , blockade , receptor , chemokine , immunology , biology , pharmacology , medicine , complement system , antibody
The complement anaphylatoxin, C5a, is excessively generated during sepsis and plays adverse roles in survival. The function of the two C5a receptors (C5aR and C5L2) remains controversial; especially C5L2, originally termed a “default receptor”. The role of each receptor was investigated in the setting of cecal ligation and puncture‐induced sepsis in mice by antibody/antagonist‐induced blockade of C5a receptors or by using knockout mice (C5aR −/− , C5L2 −/− ). Cytokine/chemokine levels in plasma were determined by quantitative proteomic analyses. The content of high mobility group box 1 protein (HMGB1) in plasma and supernatant fluids was assessed by ELISA and Western blotting. Using a “mid‐grade” level of sepsis (30% survival), blockade or absence of either C5aR or C5L2 improved survival and attenuated the buildup of proinflammatory mediators in plasma. Release of HMGB1 in vivo or secretion from phagocytes in vitro required C5L2 and signaling via mitogen‐activated protein kinase (MAPK) pathways, but was independent of C5aR. When “high‐grade” sepsis was employed (100% lethality), the only protective condition was the combined blockade of C5L2 and C5aR. These data indicate that C5aR and C5L2 contribute synergistically to harmful consequences during sepsis and that C5L2 is required for the release of HMGB1. Contrary to earlier speculation, C5L2 is a functional receptor rather than merely a “default” receptor.