Tissue-specific inducible IL-33 expression elicits features of eosinophilic esophagitis - 17/10/24

Doi : 10.1016/j.jaci.2024.08.026

Grace C. Pyon, BS ^a, Mia Y. Masuda, BS ^a,^b, Arina Putikova, BS ^a, Huijun Luo, PhD ^a, Jessica B. Gibson, BS ^a, Adelyn D. Dao, BS ^a, Danna R. Ortiz, BS ^a, Piper L. Heiligenstein, BS ^a, James J. Bonellos, BS ^a, William E. LeSuer, BS ^a, Rish K. Pai, MD, PhD ^c, Shipra Garg, MD ^d, Matthew A. Rank, MD ^a,^e, Hiroshi Nakagawa, MD, PhD ^f, Hirohito Kita, MD ^a,^b, Benjamin L. Wright, MD ^a,^e, Alfred D. Doyle, PhD ^a,^b,^⁎
^a Department of Medicine, Division of Allergy, Asthma, and Clinical Immunology, Mayo Clinic Arizona, Scottsdale, Ariz
^b Department of Immunology, Mayo Clinic, Rochester, Minn and Mayo Clinic Arizona, Scottsdale, Ariz
^c Division of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, Ariz
^d Division of Laboratory Medicine and Pathology, Phoenix Children’s Hospital, Phoenix, Ariz
^e Division of Allergy and Immunology, Phoenix Children’s Hospital, Phoenix, Ariz
^f Division of Digestive and Liver Diseases, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY

^∗Corresponding author: Alfred D. Doyle, PhD, Mayo Clinic Arizona, 13400 E Shea Blvd, Scottsdale, AZ 85259.Mayo Clinic Arizona13400 E Shea BlvdScottsdaleAZ85259

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Graphical abstract

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Abstract

Background

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).

Objective

Our objective was to develop an inducible, IL-33–dependent model of EoE and examine induction of EoE-associated pathology.

Methods

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.

Results

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.

Conclusion

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.

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Key words : IL-33, eosinophilic esophagitis, transgene, eosinophil, type 2 inflammation

Abbreviations used : BZH, DIS, dox, EA, EoE, EoEHSS, ILC2, p, pTRE, rtTA, SL, Tet, TRE