C5a initiates the inflammatory cascade in immune complex peritonitis.
Immune complex (IC)-induced inflammation is integral to the pathogenesis of several autoimmune diseases. ICs activate the complement system and interact with IgG FcgammaR. In this study, we demonstrate that activation of the complement system, specifically generation of C5a, initiates the neutrophilic inflammation in IC peritonitis. We show that ablation of C5a receptor signaling abrogates neutrophil recruitment in wild-type mice and prevents the enhancement of neutrophil migration seen in FcgammaRIIB(-/-) mice, suggesting that C5aR signaling is the crucial initial event upstream of FcgammaR signaling. We also provide evidence that C5a initiates the inflammatory cascade both directly, through C5aR-mediated effector functions on infiltrating and resident peritoneal cells, and indirectly, through shifting the balance between activating and inhibitory FcgammaRs on resident cells toward an inflammatory phenotype. We conclude that complement activation and C5a generation are prerequisites for IC-induced inflammation through activating FcgammaR, which amplifies complement-induced inflammation in autoimmunity.
Institute of Medical Microbiology, Medical School Hannover, Germany.
Jeanne
J
Godau
Tanja
T
Heller
Heiko
H
Hawlisch
Matthew
M
Trappe
Elaine
E
Howells
Jennifer
J
Best
Jörg
J
Zwirner
J Sjef
JS
Verbeek
P Mark
PM
Hogarth
Craig
C
Gerard
Nico
N
Van Rooijen
Andreas
A
Klos
J Engelbert
JE
Gessner
Jörg
J
Köhl
D000818:Animals; D002465:Cell Movement / Q000276:immunology; D019743:Chemokines, CXC / Q000276:immunology / Q000378:metabolism; D015936:Complement C5a / Q000378:metabolism*; D005260:Female; D007105:Immune Complex Diseases / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000276:immunology; D010538:Peritonitis / Q000276:immunology / Q000378:metabolism*; D044087:Receptor, Anaphylatoxin C5a / Q000276:immunology / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology
D019743:Chemokines, CXC; D044087:Receptor, Anaphylatoxin C5a; D017452:Receptors, IgG; D015936:Complement C5a