IL-4 signaling regulates the IL-9 producing mast cells (MMC9) gene expression and function in food-induced anaphylaxis in mice

Abstract

Abstract We have recently described an IL-9 producing mucosal mast cell population (MMC9s) that drives intestinal mastocytosis and food-induced anaphylaxis. The cytokine signaling pathways involved in the regulation of MMC9 function in food allergic reactions are currently not well understood. Employing a murine model of food-induced anaphylaxis and WT, gain-of-function Il4RaF709mice, and Il4Rα−/− mice we revealed an important role for IL-4 signaling in the enhancement of MMC9 frequency and this positively correlated with elevated serum levels of MCPT-1, CD4+TH2 cells, intestinal mastocytosis and increased susceptibility to food-induced anaphylaxis. Employing an adoptive transfer model of food allergy, we show direct IL-4 signaling is required for increased levels of MMC9 and development of food-induced anaphylaxis. RNA-seq analysis of purified WT, Il4RaF709and Il4Rα−/−MMC9s identified that IL-4-signaling pathway differentially regulates 238 genes that were identified to be associated with inflammatory responses and cytokine signaling processes by GO network analyses. Functional analysis revealed that IL-4 upregulates IL-9 and not IL-13 production in MMC9s. These results suggest that IL-4 signaling directly regulates MMC9 gene expression and function and onset of food-induced anaphylaxis. These studies suggest that targeting MMC9s through IL-4 signaling blockade maybe therapeutically beneficial for prevention and treatment of food allergy.