IL-10 differentially promotes mast cell responsiveness to IL-33 resulting in induction of anaphylaxis and suppression of neutrophilia

Mast cells (MCs) play critical roles in the establishment of allergic diseases. We recently demonstrated an unexpected, proinflammatory role for IL-10 in regulating MC responses. IL-10 enhanced MC activation and promoted IgE-dependent responses during food allergy. However, whether the effects of IL-10 on MCs extend to IgE-independent stimuli is not clear. Herein, we demonstrate that IL-10 plays a critical role in driving IL-33-mediated MC responses. IL-10 stimulation significantly enhanced MC expansion, ST2 expression, IL-6 and IL-13 production, and MC degranulation in IL-33-treated BMMCs. In contrast, it suppressed TNF-a in IL-33-responding cells. These differential effects also extended in vivo. In a model of IL-33-induced neutrophilia, IL-10 enhanced IL-33 responsiveness leading to increased MC activation and suppression of neutrophils via decreased TNF-a. In contrast, during IL-33-induced type 2 inflammation, IL-10 priming exacerbated MC activity, resulting in MC recruitment to various tissues, enhanced ST2 expression and induction of anaphylaxis. Our data elucidate a novel role for IL-10 as an augmenter of IL-33-mediated MC responses, with implications during both allergic diseases and other MC-dependent disorders.