Identification of FcalphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM

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.