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

Abstract

BackgroundEosinophilic 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. ObjectiveTo investigate the role of epithelial IKK{beta}/NF{kappa}B signaling in EoE pathogenesis using a mouse model with conditional Ikk{beta} knockout in esophageal epithelial cells (Ikk{beta}EEC-KO). MethodsEoE was induced in Ikk{beta}EEC-KOmice 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. ResultsIkk{beta}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 IKK{beta}/NF{kappa}B signaling pathways, with decreased expression of RELA and increased expression of IKK{beta} negative regulators. scRNA- seq analyses identified disrupted epithelial differentiation and barrier integrity, alongside increased type 2 immune responses and peptidase activity. ConclusionOur study demonstrates that loss of epithelial IKK{beta} signaling exacerbates EoE pathogenesis, highlighting the critical role of this pathway in maintaining epithelial homeostasis and preventing allergic inflammation. The Ikk{beta}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. Key MessagesO_LICritical Role of Epithelial IKK{beta}/NF{kappa}B Signaling: Loss of this signaling exacerbates EoE, causing eosinophil infiltration, basal cell hyperplasia, and tissue remodeling, highlighting its importance in esophageal health. C_LIO_LIMolecular Insights and Therapeutic Targets: scRNA-seq identified disrupted epithelial differentiation, barrier integrity, and enhanced type 2 immune responses, suggesting potential therapeutic targets for EoE. C_LIO_LIRelevance of the Ikk{beta}EEC-KO/EoE Mouse Model: This model replicates human EoE features, making it a valuable tool for studying EoE mechanisms and testing treatments, which can drive the development of effective therapies. C_LI Capsule SummaryThis study reveals the crucial role of epithelial IKK{beta}/NF{kappa}B signaling in EoE, providing insights into disease mechanisms and potential therapeutic targets, highly relevant for advancing clinical management of EoE.