Tissue-specific inducible IL-33 expression elicits features of eosinophilic esophagitis

• Published in: Journal of allergy and clinical immunology 2024-12, Vol.154 (6), p.1545-1553.e2
• Main Authors: Pyon, Grace C., Masuda, Mia Y., Putikova, Arina, Luo, Huijun, Gibson, Jessica B., Dao, Adelyn D., Ortiz, Danna R., Heiligenstein, Piper L., Bonellos, James J., LeSuer, William E., Pai, Rish K., Garg, Shipra, Rank, Matthew A., Nakagawa, Hiroshi, Kita, Hirohito, Wright, Benjamin L., Doyle, Alfred D.
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; eosinophil; eosinophilic esophagitis; Eosinophilic Esophagitis - immunology; Eosinophilic Esophagitis - metabolism; Eosinophilic Esophagitis - pathology; Esophageal Mucosa - immunology; Esophageal Mucosa - pathology; Esophagus - immunology; Esophagus - pathology; Humans; IL-33; Interleukin-13 - metabolism; Interleukin-33 - genetics; Interleukin-33 - immunology; Interleukin-33 - metabolism; Mice; Mice, Knockout; Mice, Transgenic; transgene; type 2 inflammation
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2024.08.026

[Display omitted] IL-33 is a type 2 inflammatory cytokine that is elevated in the esophageal epithelium of eosinophilic esophagitis (EoE) subjects. We previously developed a mouse model of EoE dependent on constitutive overexpression of IL-33 from the esophageal epithelium (EoE33). Our objective was to develop an inducible, IL-33–dependent model of EoE and examine induction of EoE-associated pathology. We utilized a tetracycline-inducible system to express IL-33 in the esophagus by generating 2 transgenic mice. The first (iSophagus) expresses a reverse tetracycline transactivator from the esophageal epithelium. The second (TRE33) features a tetracycline response element driving expression of IL-33. When crossed, these mice generate an inducible model of EoE (iEoE33). Mice were administered doxycycline-infused chow for up to 2 weeks. Cytokines were assessed by ELISA or bead-based multiplex analysis. T cells were assessed by flow cytometry. Pathology was assessed by histology and immunohistochemistry for IL-33, eosinophil peroxidase, CD4, and Ki-67. iEoE33 was treated with steroids and crossed with IL-13−/− mice. Doxycycline-treated iEoE33 mice demonstrated expression of IL-33 in the esophageal epithelium, and esophageal pathology including eosinophilia, CD4+ cell infiltrate, basal zone hyperplasia, and dilated intercellular spaces. These findings became pronounced on day 7 of induction, were accompanied by weight loss and esophageal thickening, and were steroid responsive and IL-13 dependent. Inducible IL-33 expression in the esophageal epithelium elicited features pathognomonic of EoE. iEoE33 enables investigation of EoE disease mechanisms as well as initiation, progression, and resolution.