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

J Allergy Clin Immunol. 2024 May;153(5):1355-1368. doi: 10.1016/j.jaci.2024.01.017. Epub 2024 Feb 3.


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-/-, eosinophil-deficient, 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 TH2 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.

Keywords: IL-33; eosinophil; eosinophilic esophagitis; transgene; type 2 inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Eosinophilic Esophagitis* / genetics
  • Eosinophilic Esophagitis* / immunology
  • Eosinophilic Esophagitis* / pathology
  • Eosinophils / immunology
  • Esophageal Mucosa / immunology
  • Esophageal Mucosa / pathology
  • Esophagus / immunology
  • Esophagus / pathology
  • Humans
  • Interleukin-1 Receptor-Like 1 Protein / genetics
  • Interleukin-1 Receptor-Like 1 Protein / metabolism
  • Interleukin-13* / genetics
  • Interleukin-13* / immunology
  • Interleukin-13* / metabolism
  • Interleukin-33* / genetics
  • Interleukin-33* / immunology
  • Interleukin-33* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic


  • Il33 protein, mouse
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-13
  • Interleukin-33
  • IL13 protein, human
  • IL33 protein, human