Functional roles for C5a receptors in sepsis.
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.
Rittirsch
Daniel
D
Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, Michigan 48109, USA.
Flierl
Michael A
MA
Nadeau
Brian A
BA
Day
Danielle E
DE
Huber-Lang
Markus
M
Mackay
Charles R
CR
Zetoune
Firas S
FS
Gerard
Norma P
NP
Cianflone
Katherine
K
Köhl
Jörg
J
Gerard
Craig
C
Sarma
J Vidya
JV
Ward
Peter A
PA
D000818:Animals; D015153:Blotting, Western; D018925:Chemokines / Q000097:blood; D003176:Complement C3 / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D024243:HMGB1 Protein / Q000097:blood; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000276:immunology*; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology*; D018805:Sepsis / Q000276:immunology*; D016019:Survival Analysis
C000594938:C5ar2 protein, mouse; D018925:Chemokines; D003176:Complement C3; D016207:Cytokines; D024243:HMGB1 Protein; D007074:Immunoglobulin G; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine