Serum IgA is considered a discrete housekeeper of the immune system with multiple anti-inflammatory functions, whereas IgA-immune complexes mediate inflammatory responses. Here, we identify FcalphaRI as a molecular device that determines the nature of IgA responses. In the absence of sustained aggregation, receptor targeting by serum IgA or anti-FcalphaRI Fab inhibits activating responses of heterologous FcgammaR or FcepsilonRI. The inhibitory mechanism involves recruitment of tyrosine phosphatase SHP-1 to FcalphaRI and impairment of Syk, LAT, and ERK phosphorylation induced by FcepsilonRI engagement. SHP-1 recruitment is dependent on ERK. Conversely, sustained aggregation of FcalphaRI by multimeric ligands stimulates cell activation by recruiting high amounts of Syk and aborting SHP-1 binding. Both types of signals require the FcRgamma-ITAM motif. Anti-FcalphaRI Fab treatment suppresses manifestations of allergic asthma in FcalphaRI transgenic mice. These findings redefine FcalphaRI as a bifunctional inhibitory/activating receptor of the immune system that mediates both anti- and proinflammatory functions of IgA.

Serum IgA is considered a discrete housekeeper of the immune system with multiple anti-inflammatory functions, whereas IgA-immune complexes mediate inflammatory responses. Here, we identify FcalphaRI as a molecular device that determines the nature of IgA responses. In the absence of sustained aggregation, receptor targeting by serum IgA or anti-FcalphaRI Fab inhibits activating responses of heterologous FcgammaR or FcepsilonRI. The inhibitory mechanism involves recruitment of tyrosine phosphatase SHP-1 to FcalphaRI and impairment of Syk, LAT, and ERK phosphorylation induced by FcepsilonRI engagement. SHP-1 recruitment is dependent on ERK. Conversely, sustained aggregation of FcalphaRI by multimeric ligands stimulates cell activation by recruiting high amounts of Syk and aborting SHP-1 binding. Both types of signals require the FcRgamma-ITAM motif. Anti-FcalphaRI Fab treatment suppresses manifestations of allergic asthma in FcalphaRI transgenic mice. These findings redefine FcalphaRI as a bifunctional inhibitory/activating receptor of the immune system that mediates both anti- and proinflammatory functions of IgA.

Inhibitory signaling is an emerging function of ITAM-bearing immunoreceptors in the maintenance of homeostasis. Monovalent targeting of the IgA Fc receptor (FcαRI or CD89) by anti-FcαRI Fab triggers potent inhibitory ITAM (ITAMi) signaling through the associated FcRγ chain (FcαRI-FcRγ ITAMi) that prevents IgG phagocytosis and IgE-mediated asthma. It is not known whether FcαRI-FcRγ 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 FcαRI-Fcγ ITAMi 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-FcαRI 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 FcαRI-FcRγ ITAMi signaling in the control of multiple heterologous or autologous inflammatory responses. They also identify anti-FcαRI Fab as a new potential therapeutic tool for preventing progression of renal inflammatory diseases.