Changes in the novel orphan, C5a receptor (C5L2), during experimental sepsis and sepsis in humans.
Sepsis is associated with extensive complement activation, compromising innate immune defenses, especially in neutrophils (PMN). Recently, a second C5a receptor (C5L2) was detected on PMN without evidence of intracellular signaling. The current study was designed to determine changes in C5L2 in blood PMN during sepsis. In vitro exposure of PMN to C5a, but not to fMLP, led to reduced content of C5L2. Following cecal ligation and puncture-induced sepsis in rats, PMN demonstrated a time-dependent decrease in C5L2. In vivo blockade of C5a during experimental sepsis resulted in preservation of C5L2. Similarly, PMN from patients with progressive sepsis showed significantly reduced C5L2 expression (n = 26), which was virtually abolished in patients who developed multiorgan failure (n = 10). In contrast, sepsis survivors exhibited retention of C5L2 (n = 12/13). The data suggest that C5L2 on PMN diminishes during sepsis due to systemic generation of C5a, which is associated with a poor prognosis.
Huber-Lang
Markus
M
Department of Traumatology, Hand and Reconstructive Surgery, University of Ulm Medical School, Germany.
Sarma
J Vidya
JV
Rittirsch
Daniel
D
Schreiber
Heike
H
Weiss
Manfred
M
Flierl
Michael
M
Younkin
Ellen
E
Schneider
Marion
M
Suger-Wiedeck
Heidemarie
H
Gebhard
Florian
F
McClintock
Shannon D
SD
Neff
Thomas
T
Zetoune
Firas
F
Bruckner
Uwe
U
Guo
Ren-Feng
RF
Monk
Peter N
PN
Ward
Peter A
PA
D000595:Amino Acid Sequence; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D002432:Cecum; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008026:Ligation; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D011677:Punctures; D051381:Rats; D020318:Rats, Long-Evans; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D011951:Receptors, Complement / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D018805:Sepsis / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality; D012772:Shock, Septic / Q000276:immunology / Q000378:metabolism / Q000401:mortality
D019138:Antibodies, Blocking; C488033:C5AR1 protein, human; C417003:C5aR2 protein, human; C496868:C5ar2 protein, rat; D008565:Membrane Proteins; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D011951:Receptors, Complement; D015936:Complement C5a