Notch signaling contributes to differentiation of mucosal mast cells and development of experimental food allergy

Skin and mucosal surfaces mediate everyday contact between the organism and its external environment. Mast cells are a member of the immune system at these barrier tissues, but interestingly, mucosal mast cells (MMCs) are both phenotypically and functionally distinct from skin mast cells. Although mast cell populations are determined by some microenvironmental factors, the factors that induce MMC differentiation are largely unknown. In this study, we show that Notch signaling contributes to the differentiation of MMCs in the intestinal mucosa. Expressions of MMC-specific proteases and CD103, a cell surface marker of MMCs, were observed in mouse bone marrow-derived mast cells (BMMCs) cultured in the presence of Notch ligands. Furthermore, we showed that Notch ligands were expressed in part of the small intestinal lamina propria cells isolated from naive BALB/c mice, and the expression of MMC-specific proteases was induced in BMMCs by coculturing with the lamina propria cells. The induced expression of the proteases was suppressed by treatment with a Notch signaling inhibitor, suggesting that Notch signaling contributes to the differentiation of MMCs in the intestinal mucosa. Therefore, we hypothesized that administration of the Notch signaling inhibitor to mice suppresses IgE-mediated hypersensitivity reactions in the intestinal tract. In a mouse model of food allergy, pharmacological inhibition of Notch signaling was demonstrated to suppress food antigen-induced mast cell hyperplasia in the intestinal mucosa, resulting in the alleviation of allergic diarrhea and systemic anaphylaxis. These results indicate that symptoms associated with experimental food allergy are alleviated by inhibition of Notch signaling.