BACKGROUND:IgE-mediated mast cell activation drives food-induced anaphylaxis in mouse models of food allergy (FA), but C57BL/6J mice are relatively resistant, whether to allergic diarrhea or systemic oral anaphylaxis. It is unclear whether this reflects a defect in mast cell activation, because these mice can produce allergen-specific IgE and respond to nonenteral allergens. OBJECTIVE:We sought to determine whether tape-stripping-induced dermal injury could promote FA in systemically sensitized C57BL/6J mice and define the contributions of mucosal mast cells (MMCs) and connective tissue mast cells (CTMCs). METHODS:C57BL/6J mice, wild-type littermates, and Mcpt5-Cre/DTA mice were subjected to systemic sensitization alone or combined tape-stripping/systemic sensitization. Anaphylaxis, mast cell hyperplasia, and mediator release were measured following oral allergen challenge. RESULTS:Systemically sensitized mice showed no impairment in IgE responses or MMC activation. However, food-induced intestinal and lethal oral anaphylaxis were observed only in tape-stripped mice. Dermal injury drove heterogeneous mast cell hyperplasia in multiple tissues, along with increased CD4 T cell- and innate lymphoid cell 2-derived IL-4 and intestinal cysteinyl leukotriene (CysLT) pathway genes. MMC and CTMC contributions were dose-dependent: repeated low-dose challenges favored leukotriene-dependent MMC responses, whereas a single high-dose challenge triggered CTMC-dependent systemic anaphylaxis. IL-4 further amplified CysLT gene expression and MMC hyperplasia, leading to CTMC-independent hypothermia. Arachidonate 5-lipoxygenase blockade reduced MMC-associated intestinal and oral anaphylaxis but did not affect CTMC-dependent systemic anaphylaxis. CONCLUSIONS:Overall, dermal injury combined with systemic sensitization promotes context-dependent FA in C57BL/6J mice through distinct mast cell subsets, with IL-4 and CysLTs shaping disease severity and phenotype.
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