title: Fc alpha receptor I activation induces leukocyte recruitment and promotes aggravation of glomerulonephritis through the FcR gamma adaptor.
abstract: Myeloid cells bear Fc receptors (FcR) that mediate inflammatory signaling through the ITAM-containing FcRgamma adaptor. They express FcRgamma-associated FcalphaRI, which modulate either activating or inhibitory signaling depending on the type of ligand interaction. The role of FcalphaRIgamma 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 FcalphaRI activation in glomerulonephritis (GN), we generated Tg mice expressing a mutated, signaling-incompetent, human FcalphaRI(R209L) that cannot associate with FcRgamma. Like FcalphaRI(wt)-Tg mice, they developed mesangial IgA deposits but not macrophage infiltration. FcalphaRI activation in FcalphaRI(wt), but not in FcalphaRI(R209L), 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 FcalphaRI(wt) Tg macrophages into non-Tg animals induced their recruitment into injured kidneys during GN development. FcalphaRI(wt) cross-linking on macrophages activated MAP kinases and production of TNF-alpha and MCP-1. Moreover, IgA-IC from IgAN patients activated FcalphaRI and induced TNF-alpha production. Thus, FcalphaRI activation mediates GN progression by initiating a cytokine/chemokine cascade that promotes leukocyte recruitment and kidney damage.
authors: INSERM U699, Paris, France.
authors: Yutaka
authors: Y
authors: Kanamaru
authors: Michelle
authors: M
authors: Arcos-Fajardo
authors: Ivan C
authors: IC
authors: Moura
authors: Toshinao
authors: T
authors: Tsuge
authors: Hélène
authors: H
authors: Cohen
authors: Marie
authors: M
authors: Essig
authors: François
authors: F
authors: Vrtovsnik
authors: Chantal
authors: C
authors: Loirat
authors: Michel
authors: M
authors: Peuchmaur
authors: Lucie
authors: L
authors: Beaudoin
authors: Pierre
authors: P
authors: Launay
authors: Agnès
authors: A
authors: Lehuen
authors: Ulrich
authors: U
authors: Blank
authors: Renato C
authors: RC
authors: Monteiro
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism* / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology*; D005921:Glomerulonephritis / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011961:Receptors, Fc / Q000378:metabolism* / Q000502:physiology; D017452:Receptors, IgG / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D015703:Antigens, CD; C036832:Fc(alpha) receptor; D011961:Receptors, Fc; D017452:Receptors, IgG