Fcα receptor I activation induces leukocyte recruitment and promotes aggravation of glomerulonephritis through the FcRγ adaptor

Myeloid cells bear Fc receptors (FcR) that mediate inflammatory signaling through the ITAM-containing FcRγ adaptor. They express FcRγ-associated FcαRI, which modulate either activating or inhibitory signaling depending on the type of ligand interaction. The role of FcαRIγ 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 FcαRI activation in glomerulonephritis (GN), we generated Tg mice expressing a mutated, signaling-incompetent, human FcαRIR209L that cannot associate with FcRγ. Like FcαRIwt-Tg mice, they developed mesangial IgA deposits but not macrophage infiltration. FcαRI activation in FcαRIwt, but not in FcαRIR209L, 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 FcαRIwt Tg macrophages into non-Tg animals induced their recruitment into injured kidneys during GN development. FcαRIwt cross-linking on macrophages activated MAP kinases and production of TNF-α and MCP-1. Moreover, IgA-IC from IgAN patients activated FcαRI and induced TNF-α production. Thus, FcαRI activation mediates GN progression by initiating a cytokine/chemokine cascade that promotes leukocyte recruitment and kidney damage.