Esophageal epithelial Ikkβ deletion promotes eosinophilic esophagitis in experimental allergy mouse model

Margarette H Clevenger; Cenfu Wei; Adam L Karami; Lia E Tsikretsis; Dustin A Carlson; John E Pandolfino; Nirmala Gonsalves; Deborah R Winter; Kelly A Whelan; Marie-Pier Tétreault

doi:10.1016/j.jaci.2024.12.1070

Esophageal epithelial Ikkβ deletion promotes eosinophilic esophagitis in experimental allergy mouse model

J Allergy Clin Immunol. 2024 Dec 24:S0091-6749(24)02385-6. doi: 10.1016/j.jaci.2024.12.1070. Online ahead of print.

Affiliations

¹ Department of Medicine, Gastroenterology and Hepatology Division, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
² Department of Cancer & Cellular Biology, Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA.
³ Department of Medicine, Rheumatology Division, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁴ Department of Medicine, Gastroenterology and Hepatology Division, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address: marie-pier.tetreault@northwestern.edu.

PMID: 39724973
DOI: 10.1016/j.jaci.2024.12.1070

Abstract

Background: Eosinophilic esophagitis (EoE) is a chronic T helper type 2 (Th2)-associated inflammatory disorder triggered by food allergens, resulting in esophageal dysfunction through edema, fibrosis, and tissue remodeling. The role of epithelial remodeling in EoE pathogenesis is critical but not fully understood.

Objective: To investigate the role of epithelial IKKβ/NFκB signaling in EoE pathogenesis using a mouse model with conditional Ikkβ knockout in esophageal epithelial cells (Ikkβ^EEC-KO).

Methods: EoE was induced in Ikkβ^EEC-KO mice through skin sensitization with MC903/Ovalbumin (OVA) followed by intraesophageal OVA challenge. Histological and transcriptional analyses were performed to assess EoE features. Single-cell RNA sequencing (scRNA-seq) was used to profile esophageal mucosal cell populations and gene expression changes.

Results: Ikkβ^EEC-KO/EoE mice exhibited hallmark EoE features, including eosinophil infiltration, intraepithelial eosinophils, microabscesses, basal cell hyperplasia, and lamina propria remodeling. RNA-seq revealed significant alterations in IKKβ/NFκB signaling pathways, with decreased expression of RELA and increased expression of IKKβ negative regulators. scRNA-seq analyses identified disrupted epithelial differentiation and barrier integrity, alongside increased type 2 immune responses and peptidase activity.

Conclusion: Our study demonstrates that loss of epithelial IKKβ signaling exacerbates EoE pathogenesis, highlighting the critical role of this pathway in maintaining epithelial homeostasis and preventing allergic inflammation. The Ikkβ^EEC-KO/EoE mouse model closely mirrors human EoE, providing a valuable tool for investigating disease mechanisms and therapeutic targets. This model can facilitate the development of strategies to prevent chronic inflammation and tissue remodeling in EoE.

Keywords: Eosinophilic esophagitis; IKKβ; Th2 response; basal cell hyperplasia; differentiation; epithelial remodeling; esophagus; inflammation; single cell RNA sequencing.