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Allergic inflammation gets “SHIP”ped out
Fc receptors bind to the Fc portion of antibodies. Fcγ receptors (FcγR) bind to IgG, whereas Fcε receptors (FcεRI) bind to IgE antibodies. Antigen recognition by FcεRI-bound IgE on mast cells and basophils triggers receptor clustering and the release of inflammatory mediators responsible for allergic symptoms. Coclustering of FceRI with FcγRIIB inhibits activation signals (cis-inhibition) by recruiting SHIP1. Malbec et al. showed that FcγRIIB also inhibited signaling through receptors with which these receptors were not coclustered, indicating that FcγRIIB can also mediate trans-inhibition. FcγRIIB limited PIP3-dependent signaling by not only the receptors involved in allergic responses, but also growth factor receptors. FcγRIIB also reduced the oncogen-induced proliferation of mastocytoma cells. These data suggest that manipulating trans-inhibition may provide a general therapy to inhibit inflammatory signaling.
Abstract
Allergic and autoimmune inflammation are associated with the activation of mast cells and basophils by antibodies against allergens or auto-antigens, respectively. Both cell types express several receptors for the Fc portion of antibodies, the engagement of which by antigen-antibody complexes controls their responses. When aggregated on the plasma membrane, high-affinity immunoglobulin E (IgE) receptors (FcεRI) and low-affinity IgG receptors (FcγRIIIA in mice, FcγRIIA in humans) induce these cells to release and secrete proinflammatory mediators, chemokines, and cytokines that account for clinical symptoms. When coaggregated with activating receptors on the same cells, other low-affinity IgG receptors (FcγRIIB in both species) inhibit mast cell and basophil activation. We found that FcγRIIB inhibited not only signals triggered by activating receptors with which they were coengaged (cis-inhibition), but also signals triggered by receptors engaged independently (trans-inhibition). Trans-inhibition acted upon the FcεRI-dependent activation of mouse mast cells, mouse basophils, and human basophils, and upon growth factor receptor (Kit)–dependent normal mouse mast cell proliferation, as well as the constitutive in vitro proliferation and the in vivo growth of oncogene (v-Abl)–transformed mastocytoma cells. Trans-inhibition was induced by receptors, whether inhibitory (FcγRIIB) or activating (FcεRI), which recruited the lipid phosphatase SHIP1. By hydrolyzing PI(3,4,5)P3, SHIP1 induced a global unresponsiveness that affected biological responses triggered by receptors that use phosphoinositide 3-kinase to signal. These data suggest that trans-inhibition controls numerous physiological and pathological processes, and that it may be used as a therapeutic tool in inflammation, especially but not exclusively, in allergy and autoimmunity.
