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

Autor: Masuda MY; Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, Ariz; Department of Immunology, Mayo Clinic, Rochester, and Mayo Clinic Arizona, Scottsdale, Ariz., Pyon GC; Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, Ariz., Luo H; Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, Ariz., LeSuer WE; Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, Ariz., Putikova A; Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, Ariz., Dao A; Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, Ariz., Ortiz DR; Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, Ariz., Schulze AR; Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, Ariz., Fritz N; School of Biological and Health Systems Engineering, Arizona State University, Tempe, Ariz., Kobayashi T; Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, Ariz., Iijima K; Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, Ariz., Klein-Szanto AJ; Histopathology Facility, Fox Chase Cancer Center, Philadelphia, Pa., Shimonosono M; Division of Digestive and Liver Diseases, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY., Flashner S; Division of Digestive and Liver Diseases, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY., Morimoto M; Division of Digestive and Liver Diseases, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY., Pai RK; Division of Pathology and Laboratory Medicine, Mayo Clinic Arizona, Scottsdale, Ariz., Rank MA; Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, Ariz; Division of Allergy and Immunology, Phoenix Children's Hospital, Phoenix, Ariz., Nakagawa H; Division of Digestive and Liver Diseases, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY., Kita H; Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, Ariz; Department of Immunology, Mayo Clinic, Rochester, and Mayo Clinic Arizona, Scottsdale, Ariz., Wright BL; Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, Ariz; Division of Allergy and Immunology, Phoenix Children's Hospital, Phoenix, Ariz., Doyle AD; Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, Ariz. Electronic address: doyle.alfred@mayo.edu.
Jazyk: angličtina
Zdroj: The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2024 May; Vol. 153 (5), pp. 1355-1368. Date of Electronic Publication: 2024 Feb 03.
DOI: 10.1016/j.jaci.2024.01.017
Abstrakt: 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 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.
(Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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