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.

IntroductionThe receptor specific for the IgA Fc region (Fc␣RI or CD89) is expressed on blood myeloid cells, including monocyte/macrophages, dendritic cells, Kupffer cells, neutrophils, and eosinophils. 1 It transmits IgA-mediated effector functions via an IgA-binding module (K a about 10 6 M Ϫ1 ) that can be expressed with or without physical association with the disulfide-linked signaling adaptor FcR␥. 2,3 The FcR␥-associated receptor has signaling functions that involve an immunoreceptor tyrosine-based activation motif (ITAM), consisting of a conserved sequence that is present in the cytoplasmic domain of FcR␥ and is shared by different signaling subunits associated with receptors such as TCR and BCR and other FcRs. Although the ITAM was initially reported to mediate activating responses, recent data suggest that, in certain conditions, this motif can also trigger inhibitory responses mediated by a variety of receptors. [4][5][6] The latter include Fc␣RI, a dual-function receptor that can mediate both activating and inhibitory responses depending on the type of interaction with its ligand. Sustained multimeric aggregation mediates activation of target-cell functions, such as superoxide production, cytokine release, and antigen presentation. 7-9 Monomeric targeting with IgA or with a variety of anti-Fc␣RI (A77, A59, or A62, but not A3) Fab fragments triggers an inhibitory response to heterologous immunoreceptors such as Fc⑀RI and Fc␥R. 5 Like the activating functions, the inhibitory cross-talk is dependent on the FcR␥ ITAM. However, in contrast to receptors bearing an immunoreceptor tyrosine-based inhibitory motif (ITIM), such as FcR␥IIB, 10 the inhibitory signal does not require coaggregation. Monomeric targeting of Fc␣RI also has powerful anti-inflammatory activity in vivo because administration of anti-Fc␣RI Fab suppresses manifestations of allergic asthma in Fc␣RI transgenic mice. 5 Activation of certain FcRs also promotes cell death. Thus, Fc␥RIIB expressed on B cells not only terminates the activation signals of coengaged receptors, via an ITIM-dependent mechanism, but, in case of isolated aggregation, is also able to trigger an apoptotic response. 11 The latter involves ITIM and Src homology 2 domain-containing inositide phosphatase (SHIP)-independent and c-abl-family kinase-dependent pathways. [12][13][14] Recruitment of the Src homology 2 domain-containing phosphatase (SHP)-1 to the B-and T-cell antigen receptors (BCR and TCR) was also shown to negatively correlate with the induction of apoptosis. 12,15 Indeed, SHP-1-deficient mice are unusually susceptible to clonal deletion of their B-and T-cell compartment. [15][16][17] Although the precise mechanisms whereby SHP-1 negatively regulates apoptosis remains unknown, a possible hypothesis is that SHP-1 raises the threshold required for antigen receptor signaling spread thereby linking it to other biologic outcomes such as cell death.Incubation of neutrophils with immobilized IgA or secretory IgA also induces apopotosis. 18 This likely involves Fc␣RI, t...