The harmful role of c5a on innate immunity in sepsis.
There is accumulating evidence in humans and in experimental sepsis that robust activation of the complement system occurs along with development of defects in the innate immune system. In this report we review evidence that the complement activation product, C5a, appears in the plasma of rodents following cecal ligation and puncture (CLP). C5a interacts with its receptors (C5aR, C5L2) on phagocytes (polymorphonuclear neutrophils, PMNs, macrophages), ultimately paralyzing the ERK1/2 pathway of the mitogen-activated protein kinase signaling pathway. C5a is also interactive with its receptors on a variety of other cell types in various organs. Interaction of C5a with receptors on PMNs results in compromised innate immunity, with intense suppression of phagocytosis, chemotaxis and the respiratory burst. Endothelial cells acquire a pro-inflammatory phenotype (increased ICAM-1 and tissue factor expression), while macrophages are primed and produce large amounts of cytokines/chemokines. All of these outcomes are C5a and C5a receptor dependent. CLP also unleashes activation of clotting (and fibrinolytic) factors in a C5a-dependent manner. Finally, thymocytes upregulate C5aR and react with C5a, resulting in apoptosis via the intrinsic (mitochondrial) pathway. Collectively, these findings suggest that interception of C5a in sepsis preserves innate immune functions and may be a strategy for treatment of septic humans.
Ward
Peter A
PA
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-5602, USA. pward@umich.edu
D000818:Animals; D015936:Complement C5a / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D044087:Receptor, Anaphylatoxin C5a / Q000276:immunology / Q000378:metabolism; D018805:Sepsis / Q000276:immunology* / Q000503:physiopathology*; D015398:Signal Transduction
D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a