IL-27 signaling negatively regulates FceRI-mediated mast cell activation and allergic response

IL-27 is a member of the IL-12 family, exerting both anti- and pro-inflammatory activity in a cell-dependent and disease context-specific manner. Antigen-mediated cross-linking of IgE on mast cells triggers a signaling cascade that results in mast cell degranulation and proinflammatory cytokine production, which are key effectors in allergic reactions. Here, we show that the activation of mast cells is negatively regulated by IL-27 signaling. We found that mice lacking IL-27R alpha (WSX-1) displayed increased sensitivity to IgE-mediated skin allergic response and chronic airway inflammation. The bone marrow-derived mast cells (BMMCs) of IL-27R alpha-deficient mouse showed greater high-affinity receptor Fc epsilon RI (Fc epsilon RI)-mediated activation with significantly enhanced degranulation and cytokine production. Mechanistically, the dysregulated signaling in IL-27R alpha(-/-) mast cells is associated with increased activation of Grb2-PLC-gamma 1-SLP-76, PI3K/Akt/I kappa B alpha signaling and decreased phosphorylation level of SH2 domain-containing protein phosphatase1 (SHP1). Furthermore, IL-27 treatment could inhibit mast cell activation directly, and retrovirus-based IL-27 expression in lung attenuated the airway inflammation in mice. Collectively, our findings reveal that IL-27 signaling negatively regulates mast cell activation and its mediated allergic response.