Pharmacological inhibition of Notch signaling suppresses food antigen-induced mucosal mast cell hyperplasia

Publication date: Available online 16 July 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Asuka Honjo, Nobuhiro Nakano, Susumu Yamazaki, Mutsuko Hara, Koichiro Uchida, Jiro Kitaura, Chiharu Nishiyama, Hideo Yagita, Yoshikazu Ohtsuka, Hideoki Ogawa, Ko Okumura, Toshiaki Shimizu
BackgroundMucosal mast cells (MMCs) play a central role in the development of symptoms associated with IgE-mediated food allergy. Recently, Notch2-mediated signaling was shown to be involved in proper MMC distribution in the intestinal tract.ObjectiveThis study aimed to clarify the mechanism by which Notch signaling regulates MMC distribution in the intestinal mucosa. Furthermore, pharmacological inhibition of Notch signaling was evaluated as a treatment for symptoms associated with experimental food allergy.MethodsBone marrow-derived mast cells (BMMCs) generated from mice were cultured with Notch ligands, and then expression of genes associated with mucosal mast cells was measured in the cells. In addition, the effect of an inhibitor of Notch signaling on food antigen-induced allergic reactions was examined in a mouse model of food allergy.ResultsNotch signaling induced MMC differentiation through up-regulation of expression of genes characteristic of MMCs in the presence of IL-3. Some lamina propria cells isolated from the mouse small intestine expressed Notch ligands and were able to up-regulate MMC markers in BMMCs through Notch signaling. In a mouse model of food allergy, administration of a Notch signaling inhibitor led to suppression of food antigen-induced hyperplasia of intestinal MMCs, resulting in an alleviation of allergic diarrhea and systemic anaphylaxis.ConclusionNotch signaling contributes to differentiation and accumulation of MMCs in the intestinal mucosa. Thus, inhibition of Notch signaling alleviates symptoms associated with experimental food allergy. These results raise the possibility that Notch signaling in mast cells is a novel target for therapy in food allergy.

Teaser

Notch signaling contributes to the maturation and accumulation of mucosal mast cells in the intestinal tract. Therefore, pharmacological inhibition of Notch signaling suppresses food antigen-induced mucosal mast cell hyperplasia in the intestinal tract.


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