Critical but overlapping role of FcgammaRIII and FcgammaRIV in activation of murine neutrophils by immobilized immune complexes.
Immune complex-induced activation of neutrophils through cell surface FcRs plays a central role in the pathogenesis of autoimmune inflammatory diseases. These diseases are often modeled using genetically modified mice. However, in contrast to the number of studies on human cells, the identity of FcRs involved in immune complex activation of murine neutrophils is at present unknown. Furthermore, little is known about the cellular functions mediated by the recently identified murine FcgammaRIV. In this study, we tested the identity of FcRs involved in the activation of neutrophils by plate-bound immune complexes, using various knockout mouse strains, function-blocking mAbs, or the combination of both approaches. Activation of murine neutrophils by immobilized IgG immune complexes was abrogated in FcR gamma-chain-deficient cells, but not by the single or combined deficiency of the gamma-chain-associated FcgammaRI and FcgammaRIII, or by blocking Abs against either FcgammaRIII or FcgammaRIV alone. However, treatment of FcgammaRIII-deficient neutrophils with FcgammaRIV-blocking Abs or simultaneous blocking of FcgammaRIII and FcgammaRIV in wild-type cells completely inhibited the immune complex-induced cellular responses. In parallel studies, activation of human neutrophils by immobilized immune complexes was abrogated by blocking Abs against either FcgammaRIIA or FcgammaRIIIB alone. Taken together, neutrophil activation by immobilized immune complexes requires the murine FcgammaRIII/FcgammaRIV or the human FcgammaRIIA/FcgammaRIIIB molecules. Although both of the two human receptors are required for this response, the two murine receptors play overlapping, redundant roles. These results promote our understanding of autoimmune diseases and identify an IgG-dependent cellular function of FcgammaRIV.
Jakus
Zoltán
Z
Department of Physiology, School of Medicine, Semmelweis University, Budapest, Hungary.
Németh
Tamás
T
Verbeek
J Sjef
JS
Mócsai
Attila
A
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000936:Antigen-Antibody Complex / Q000378:metabolism* / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D000906:Antibodies; D000936:Antigen-Antibody Complex; D015703:Antigens, CD; C080568:Fc gamma receptor IIA; C485700:Fcgr3 protein, mouse; C522404:Fcgr4 protein, mouse; D017452:Receptors, IgG