Epithelial overexpression of IL-33 induces eosinophilic esophagitis dependent on IL-13

Background: Eosinophilic esophagitis (EoE) is an increasingly common inflammatory condition of the esophagus; however, the underlying immunologic mechanisms remain poorly understood. The epithelium -derived cytokine IL -33 is associated with type 2 immune responses and elevated in esophageal biopsy specimens from patients with EoE. Objective: We hypothesized that overexpression of IL -33 by the esophageal epithelium would promote the immunopathology of EoE. Methods: We evaluated the functional consequences of esophageal epithelial overexpression of a secreted and active form of IL -33 in a novel transgenic mouse, EoE33. EoE33 mice were analyzed for clinical and immunologic phenotypes. Esophageal contractility was assessed. Epithelial cytokine responses were analyzed in three-dimensional organoids. EoE33 phenotypes were further characterized in ST2 - / - , eosinophildeficient, and IL -13 - / - mice. Finally, EoE33 mice were treated with dexamethasone. Results: EoE33 mice displayed ST2-dependent, EoE-like pathology and failed to thrive. Esophageal tissue remodeling and inflammation included basal zone hyperplasia, eosinophilia, mast cells, and T H 2 cells. Marked increases in levels of type 2 cytokines, including IL -13, and molecules associated with immune responses and tissue remodeling were observed. Esophageal organoids suggested reactive epithelial changes. Genetic deletion of IL -13 in EoE33 mice abrogated pathologic changes in vivo . EoE33 mice were responsive to steroids. Conclusions: IL -33 overexpression by the esophageal epithelium generated immunopathology and clinical phenotypes resembling human EoE. IL -33 may play a pivotal role in the etiology of EoE by activating the IL -13 pathway. EoE33 mice are a robust experimental platform for mechanistic investigation and translational discovery. (J Allergy Clin Immunol 2024;153:1355-68.)