Inhibitory ITAM signaling by FcαRI-FcRγ chain controls multiple activating renal inflammation
Inhibitory ITAM signaling by FcαRI-FcRγ chain controls multiple activating renal inflammation
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DOI：
10.4049/jimmunol.180.4.2669
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发表时间：
2008-02-15
影响因子：
4.4
通讯作者：
Monteiro, Renato C.
中科院分区：
文献类型：
--
作者：
Kanamaru, Yutaka;Pfirsch, Sverine;Monteiro, Renato C.
Inhibitory signaling is an emerging function of ITAM-bearing immunoreceptors in the maintenance of homeostasis. Monovalent targeting of the IgA Fc receptor (Fc alpha RI or CD89) by anti-Fe alpha RI Fab triggers potent inhibitory ITAM (ITAM(i)) signaling through the associated FeR gamma chain (Fc alpha RI-FcR gamma ITAM(i)) that prevents IgG phagocytosis and IgE-mediated asthma. It is not known whether Fc alpha RI-FcR gamma ITAMi 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 Fc alpha RI-Fc gamma 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-Fc alpha RI 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 LIPS 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 Fc alpha RI-FcR gamma ITAM(i) signaling in the control of multiple heterologous or autologous inflammatory responses. They also identify anti-Fc alpha RI Fab as a new potential therapeutic tool for preventing progression of renal inflammatory diseases.
