Overexpression of IL-18 promotes iNKT cell mediated eosinophilic esophageal inflammation in experimental murine model of eosinophilic esophagitis (HYP7P.257)

Abstract

Abstract Elevated level of IL-18 is reported in a number of allergic diseases and we earlier reported induced blood IL-18 and esophageal IL-18Rα mRNA in human EoE. Therefore, the current study focuses on the hypothesis that allergen-induced IL-18 and its receptor (IL-18Rα) positive cells may have an important role in EoE pathogenesis. Accordingly, we examined the blood IL-18 and esophageal IL-18Rα mRNA levels in aeroallergen and food allergen induced experimental mouse model of EoE. Herein, we demonstrate that blood IL-18 protein and esophageal IL-18Rα mRNA are induced in the mouse model of EoE and the source of induced esophageal IL-18Rα transcript are iNKT cells. We report that intranasal delivery of rIL-18 induces both mast cells and eosinophilic inflammation in the esophagus. Furthermore, to establish the significance of IL-18 in EoE pathogenesis, we next examined DOX-inducible rtTA-CC10-IL-18 bitransgenic mice that have significantly induced IL-18 protein in the esophagus. Our analysis indicated that DOX exposed IL-18 tg mice develop most of the characteristics of EoE, such as esophageal intraepithelial eosinophilia, increased mast cells and esophageal remodeling including fibrosis. Mechanistically, we show that IL-5 gene-deficient mice and iNKT cell-deficient (CD1d null) mice do not induce EoE in response to IL-18 intranasal challenge. Taken together, we provide evidences that allergen induced IL-18 has a significant role in promoting IL-5 and iNKT dependent EoE pathogenesis.