The soluble isoform of FcɛRI, the high‐affinity IgE receptor (sFcεRI), is a protein of the IgE network with poorly defined functions.

To define cellular sources and signals that result in the production of human sFcεRI and study its in vivo functions.

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.

Antigen‐specific cross‐linking of IgE‐loaded FcɛRI on MelJuso cells that express the trimeric or tetrameric receptor isoform induced the production of sFcεRI. Using MCs and moDCs, we confirmed that IgE/FcɛRI activation induces sFcɛRI release. We demonstrated that generation of sFcɛRI requires Src phosphorylation and endo/lysosomal acidification. In experimental mouse models, sFcɛRI diminishes the severity of IgE‐mediated anaphylaxis. BATs confirmed that, comparable to the anti‐IgE monoclonal antibody omalizumab, sFcɛRI is an inhibitor of the human innate IgE effector axis, implying that sFcɛRI and omalizumab potentially inhibit each other in vivo.

sFcɛRI is produced after antigen‐specific IgE/FcɛRI‐mediated activation signals and functions as an endogenous inhibitor of IgE loading to FcɛRI and IgE‐mediated activation. Our results imply, therefore, that sFcɛRI contributes to a negative regulatory feedback loop that aims at preventing overshooting responses after IgE‐mediated immune activation.