Clevenger Margarette H, Wei Cenfu, Karami Adam L, Tsikretsis Lia E, Carlson Dustin A, Pandolfino John E, Gonsalves Nirmala, Winter Deborah R, Whelan Kelly A, Tétreault Marie-Pier
Department of Medicine, Gastroenterology and Hepatology Division, Northwestern University Feinberg School of Medicine, Chicago, Ill.
Department of Cancer & Cellular Biology, Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pa.
J Allergy Clin Immunol. 2025 Apr;155(4):1276-1289. doi: 10.1016/j.jaci.2024.12.1070. Epub 2024 Dec 24.
Eosinophilic esophagitis (EoE) is a chronic T2-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.
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).
EoE was induced in Ikkβ 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.
Ikkβ/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.
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/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.
嗜酸性粒细胞性食管炎（EoE）是一种由食物过敏原引发的慢性2型相关炎症性疾病，通过水肿、纤维化和组织重塑导致食管功能障碍。上皮重塑在EoE发病机制中的作用至关重要，但尚未完全明确。
我们使用食管上皮细胞条件性Ikkβ基因敲除小鼠模型（Ikkβ），研究上皮IKKβ/NF-κB信号通路在EoE发病机制中的作用。
通过用MC903/卵清蛋白进行皮肤致敏，随后进行食管内卵清蛋白激发，在Ikkβ小鼠中诱导EoE。进行组织学和转录分析以评估EoE特征。使用单细胞RNA测序对食管黏膜细胞群体和基因表达变化进行分析。
Ikkβ/EoE小鼠表现出EoE的典型特征，包括嗜酸性粒细胞浸润、上皮内嗜酸性粒细胞、微脓肿、基底细胞增生和固有层重塑。RNA测序显示IKKβ/NF-κB信号通路有显著改变，RELA表达降低，IKKβ负调控因子表达增加。测序分析确定上皮分化和屏障完整性受损，同时2型免疫反应和肽酶活性增加。
上皮IKKβ信号通路的缺失加剧了EoE的发病机制，突出了该通路在维持上皮稳态和预防过敏性炎症中的关键作用。Ikkβ/EoE小鼠模型与人类EoE非常相似，为研究疾病机制和治疗靶点提供了有价值的工具。该模型有助于制定预防EoE慢性炎症和组织重塑的策略。
