RESUMO
BACKGROUND: The soluble isoform of FcÉRI, the high-affinity IgE receptor (sFcεRI), is a protein of the IgE network with poorly defined functions. OBJECTIVE: To define cellular sources and signals that result in the production of human sFcεRI and study its in vivo functions. METHODS: FcεRI-transfected human cell lines (MelJuso), human monocyte-derived dendritic cells (moDCs), and murine bone marrow-derived mast cells (MC) were stimulated by FcεRI cross-linking and release of sFcεRI was analyzed (ELISA, Western Blot). Lysosomal-associated membrane protein 1 degranulation assays and human basophil activation tests (BATs) were used to study IgE-dependent activation. Recombinant sFcεRI (rsFcεRI) was used to assess its role in murine models of anaphylaxis with WT (wild-type) and IgE-/- (IgE-deficient) mice. RESULTS: Antigen-specific cross-linking of IgE-loaded FcÉRI on MelJuso cells that express the trimeric or tetrameric receptor isoform induced the production of sFcεRI. Using MCs and moDCs, we confirmed that IgE/FcÉRI activation induces sFcÉRI release. We demonstrated that generation of sFcÉRI requires Src phosphorylation and endo/lysosomal acidification. In experimental mouse models, sFcÉRI diminishes the severity of IgE-mediated anaphylaxis. BATs confirmed that, comparable to the anti-IgE monoclonal antibody omalizumab, sFcÉRI is an inhibitor of the human innate IgE effector axis, implying that sFcÉRI and omalizumab potentially inhibit each other in vivo. CONCLUSION: sFcÉRI is produced after antigen-specific IgE/FcÉRI-mediated activation signals and functions as an endogenous inhibitor of IgE loading to FcÉRI and IgE-mediated activation. Our results imply, therefore, that sFcÉRI contributes to a negative regulatory feedback loop that aims at preventing overshooting responses after IgE-mediated immune activation.