Inhibitory ITAM signaling by Fc alpha RI-FcR gamma chain controls multiple activating responses and prevents renal inflammation.
Inhibitory signaling is an emerging function of ITAM-bearing immunoreceptors in the maintenance of homeostasis. Monovalent targeting of the IgA Fc receptor (FcalphaRI or CD89) by anti-FcalphaRI Fab triggers potent inhibitory ITAM (ITAM(i)) signaling through the associated FcRgamma chain (FcalphaRI-FcRgamma ITAM(i)) that prevents IgG phagocytosis and IgE-mediated asthma. It is not known whether FcalphaRI-FcRgamma ITAM(i) signaling controls receptors that do not function through an ITAM and whether this inhibition requires Src homology protein 1 phosphatase. We show in this study that FcalphaRI-Fcgamma ITAM(i) signals depend on Src homology protein 1 phosphatase to target multiple non-ITAM-bearing receptors such as chemotactic receptors, cytokine receptors, and TLRs. We found that anti-FcalphaRI Fab treatment in vivo reduced kidney inflammation in models of immune-mediated glomerulonephritis and nonimmune obstructive nephropathy by a mechanism that involved decreased inflammatory cell infiltration and fibrosis development. This treatment also prevented ex vivo LPS activation of monocytes from patients with lupus nephritis or vasculitis, as well as receptor activation through serum IgA complexes from IgA nephropathy patients. These findings point to a crucial role of FcalphaRI-FcRgamma ITAM(i) signaling in the control of multiple heterologous or autologous inflammatory responses. They also identify anti-FcalphaRI Fab as a new potential therapeutic tool for preventing progression of renal inflammatory diseases.
Kanamaru
Yutaka
Y
INSERM Unité 699, Universite Paris 7-Denis Diderot, Faculte de Medecine, Site Xavier Bichat, 16 rue Henri Huchard, Paris, France.
Pfirsch
Séverine
S
Aloulou
Meryem
M
Vrtovsnik
François
F
Essig
Marie
M
Loirat
Chantal
C
Deschênes
Georges
G
Guérin-Marchand
Claudine
C
Blank
Ulrich
U
Monteiro
Renato C
RC
D020816:Amino Acid Motifs / Q000276:immunology; D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D045744:Cell Line, Tumor; D002464:Cell Migration Inhibition / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D005922:Glomerulonephritis, IGA / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000473:pathology; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011961:Receptors, Fc / Q000502:physiology; D017452:Receptors, IgG / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*
D015703:Antigens, CD; C036832:Fc(alpha) receptor; D011961:Receptors, Fc; D017452:Receptors, IgG; D011971:Receptors, Immunologic