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Critical but Overlapping Role of FcRIII and FcRIV in Activation of Murine Neutrophils by Immobilized Immune Complexes^1,2

Zoltán Jakus^*, Tamás Németh^*, J. Sjef Verbeek and Attila Mócsai^3,*

^* Department of Physiology, School of Medicine, Semmelweis University, Budapest, Hungary; and Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

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 FcRIV. 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 -chain-deficient cells, but not by the single or combined deficiency of the -chain-associated FcRI and FcRIII, or by blocking Abs against either FcRIII or FcRIV alone. However, treatment of FcRIII-deficient neutrophils with FcRIV-blocking Abs or simultaneous blocking of FcRIII and FcRIV 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 FcRIIA or FcRIIIB alone. Taken together, neutrophil activation by immobilized immune complexes requires the murine FcRIII/FcRIV or the human FcRIIA/FcRIIIB 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 FcRIV.

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¹ Z.J. and A.M. designed the work, interpreted the results, and wrote the paper. Z.J., T.N., and A.M. performed the experiments and analyzed the data. J.S.V. provided experimental tools (FcRI and FcRIII-deficient mice). A.M. supervised the project.

² This work was supported by the Hungarian Scientific Research Fund (OTKA T046409, to A.M.), the Hungarian Office for Research and Technology (NKFP-A1-0069/2006, to A.M.), and the U.S. National Institutes of Health (R03 TW006831, to A.M.). A.M. is an International Senior Research Fellow of the Wellcome Trust and a European Molecular Biology Organization/Howard Hughes Medical Institute Scientist. Z.J. and A.M. are recipients of Bolyai Research Fellowships from the Hungarian Academy of Sciences.

³ Address correspondence and reprint requests to Dr. Attila Mócsai, Department of Physiology, School of Medicine, Semmelweis University, P. O. Box 259, 1444 Budapest, Hungary. E-mail address: mocsai{at}puskin.sote.hu

⁴ Abbreviations used in this paper: HSA, human serum albumin; Lfr, lactoferrin; DAP12, DNAX-activating protein of 12 kDa; CB, cytochalasin B.

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