title: Changes and regulation of the C5a receptor on neutrophils during septic shock in humans.
abstract: During experimental sepsis, excessive generation of the anaphylatoxin C5a results in reduction of the C5a receptor (C5aR) on neutrophils. These events have been shown to result in impaired innate immunity. However, the regulation and fate of C5aR on neutrophils during sepsis are largely unknown. In contrast to 30 healthy volunteers, 60 patients in septic shock presented evidence of complement activation with significantly increased serum levels of C3a, C5a, and C5b-9. In the septic shock group, the corresponding decrease in complement hemolytic activity distinguished survivors from nonsurvivors. Neutrophils from patients in septic shock exhibited decreased C5aR expression, which inversely correlated with serum concentrations of C-reactive protein (CRP) and clinical outcome. In vitro exposure of normal neutrophils to native pentameric CRP led to a dose- and time-dependent loss of C5aR expression on neutrophils, whereas the monomeric form of CRP, as well as various other inflammatory mediators, failed to significantly alter C5aR levels on neutrophils. A circulating form of C5aR (cC5aR) was detected in serum by immunoblotting and a flow-based capture assay, suggestive of an intact C5aR molecule. Levels of cC5aR were significantly enhanced during septic shock, with serum levels directly correlating with lethality. The data suggest that septic shock in humans is associated with extensive complement activation, CRP-dependent loss of C5aR on neutrophils, and appearance of cC5aR in serum, which correlated with a poor outcome. Therefore, cC5aR may represent a new sepsis marker to be considered in tailoring individualized immune-modulating therapy.
authors.affiliation: Department of Orthopedic Trauma, Hand-, Plastic-, and Reconstructive Surgery, University Hospital Ulm, 89081 Ulm, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Unnewehr
authors.forename: Daniel
authors.initials: D
authors.lastname: Rittirsch
authors.forename: J Vidya
authors.initials: JV
authors.lastname: Sarma
authors.forename: Firas
authors.initials: F
authors.lastname: Zetoune
authors.forename: Michael A
authors.initials: MA
authors.lastname: Flierl
authors.forename: Mario
authors.initials: M
authors.lastname: Perl
authors.forename: Stephanie
authors.initials: S
authors.lastname: Denk
authors.forename: Manfred
authors.initials: M
authors.lastname: Weiss
authors.forename: Marion E
authors.initials: ME
authors.lastname: Schneider
authors.forename: Peter N
authors.initials: PN
authors.lastname: Monk
authors.forename: Thomas
authors.initials: T
authors.lastname: Neff
authors.forename: Michael
authors.initials: M
authors.lastname: Mihlan
authors.forename: Holger
authors.initials: H
authors.lastname: Barth
authors.forename: Florian
authors.initials: F
authors.lastname: Gebhard
authors.forename: Peter A
authors.initials: PA
authors.lastname: Ward
authors.forename: Markus
authors.initials: M
authors.lastname: Huber-Lang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000037:antagonists & inhibitors / Q000097:blood*; D012772:Shock, Septic / Q000097:blood* / Q000276:immunology* / Q000401:mortality; D013534:Survival
chemical_list: C488033:C5AR1 protein, human; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement