Abstract
BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic T(H)2-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: We investigated the role of epithelial IKKβ/NF-κB 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 followed by intraesophageal ovalbumin challenge. Histologic and transcriptional analyses were performed to assess EoE features. Single-cell RNA sequencing 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 sequencing revealed significant alterations in IKKβ/NF-κB signaling pathways, with decreased expression of RELA and increased expression of IKKβ-negative regulators. Sequencing analyses identified disrupted epithelial differentiation and barrier integrity alongside increased type 2 immune responses and peptidase activity. CONCLUSION: 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.