Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 37, Issue 4, Pages 1116-1128Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/eji.200636826
Keywords
Fc receptors; IgA; IgA nephropathy; signaling
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Myeloid cells bear Fc receptors (FcR) that mediate inflammatory signaling through the ITAM-containing FcR gamma adaptor. They express FcR gamma-associated Fc alpha RI, which modulate either activating or inhibitory signaling depending on the type of ligand interaction. The role of Fc alpha RI gamma in disease progression remains unknown, notably in IgA nephropathy (IgAN), one of major causes of end-stage renal disease, in which large amounts of circulating IgA-immune complexes (IC) may mediate receptor activation. To analyze the involvement of Fc alpha RI activation in glornerulonephritis (GN), we generated Tg mice expressing a mutated, signaling-incompetent, human Fc alpha RIR209L that cannot associate with FcR gamma. Like Fc alpha RIwt-Tg mice, they developed mesangial IgA deposits but not macrophage infiltration. Fc alpha RI activation in Fc alpha RIwt, but not in Fc alpha RIR209L, Tg mice resulted in marked inflammation with severe proteinuria and leukocyte infiltration in spontaneous IgAN or anti-glomerular basement membrane Ab-induced GN models. Receptor triggering of syngenically transferred Fc alpha RIwt Tg macrophages into non-Tg animals induced their recruitment into injured kidneys during GN development. Fc alpha RIwt cross-linking on macrophages activated MAP kinases and production of TNF-alpha and MCP-1. Moreover, IgA-IC from IgAN patients activated FcaRI and induced TNF-alpha production. Thus, Fc alpha RI activation mediates GN progression by initiating a cytokine/ chemokine cascade that promotes leukocyte recruitment and kidney damage.
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