Identification of FcαRI as an Inhibitory Receptor that Controls Inflammation Dual Role of FcRγ ITAM

AbstractSerum 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 FcαRI as a molecular device that determines the nature of IgA responses. In the absence of sustained aggregation, receptor targeting by serum IgA or anti-FcαRI Fab inhibits activating responses of heterologous FcγR or FcϵRI. The inhibitory mechanism involves recruitment of tyrosine phosphatase SHP-1 to FcαRI and impairment of Syk, LAT, and ERK phosphorylation induced by FcϵRI engagement. SHP-1 recruitment is dependent on ERK. Conversely, sustained aggregation of FcαRI by multimeric ligands stimulates cell activation by recruiting high amounts of Syk and aborting SHP-1 binding. Both types of signals require the FcRγ-ITAM motif. Anti-FcαRI Fab treatment suppresses manifestations of allergic asthma in FcαRI transgenic mice. These findings redefine FcαRI as a bifunctional inhibitory/activating receptor of the immune system that mediates both anti- and proinflammatory functions of IgA