IL-10 differentially promotes mast cell responsiveness to IL-33 resulting in induction of anaphylaxis and suppression of neutrophilia
Saurav Ranjitkar, Dylan Krajewski, Chelsea Garcia, Stephanie Polukort, Jeffrey Rovatti, Mohamed Mire, Caitlin Tedeschi, Christopher Blesso, Evan Jellison, Sallie Schneider, John Ryan, Clinton MathiasAbstract
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.