Epithelial HIF-1[alpha]/claudin-1 axis regulates barrier dysfunction in eosinophilic esophagitis

Epithelial barrier dysfunction is a significant factor in many allergic diseases, including eosinophilic esophagitis (EoE). Infiltrating leukocytes and tissue adaptations increase metabolic demands and decrease oxygen availability at barrier surfaces. Understanding of how these processes impact barr...

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Published inThe Journal of clinical investigation Vol. 129; no. 8; pp. 3224 - 3235
Main Authors Masterson, Joanne C, Biette, Kathryn A, Hammer, Juliet A, Nguyen, Nathalie, Capocelli, Kelley E, Saeedi, Bejan J, Harris, Rachel F, Fernando, Shahan D, Hosford, Lindsay B, Kelly, Caleb J, Campbell, Eric L, Ehrentraut, Stefan F, Ahmed, Faria N, Nakagawa, Hiroshi, Lee, James J, McNamee, Eoin N, Glover, Louise E, Colgan, Sean P, Furuta, Glenn T
Format Journal Article
LanguageEnglish
Published American Society for Clinical Investigation 01.08.2019
Subjects
Allergy
Analysis
Esophagitis
Genetic engineering
Inflammation
Colorado
Ireland
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Summary:Epithelial barrier dysfunction is a significant factor in many allergic diseases, including eosinophilic esophagitis (EoE). Infiltrating leukocytes and tissue adaptations increase metabolic demands and decrease oxygen availability at barrier surfaces. Understanding of how these processes impact barrier is limited, particularly in allergy. Here, we identified a regulatory axis whereby the oxygen-sensing transcription factor HIF-1[alpha] orchestrated epithelial barrier integrity, selectively controlling tight junction CLDN1 (claudin-1). Prolonged experimental hypoxia or HIF1A knockdown suppressed HIF-1[alpha]-dependent claudin-1 expression and epithelial barrier function, as documented in 3D organotypic epithelial cultures. L2-IL[5.SUP.OXA] mice with EoE-relevant allergic inflammation displayed localized eosinophil oxygen metabolism, tissue hypoxia, and impaired claudin-1 barrier via repression of HIF-1[alpha]/claudin-1 signaling, which was restored by transgenic expression of esophageal epithelial-targeted stabilized HIF-1[alpha]. EoE patient biopsy analysis identified a repressed HIF-1[alpha]/claudin-1 axis, which was restored via pharmacologic HIF-1[alpha] stabilization ex vivo. Collectively, these studies reveal HIF-1[alpha]'s critical role in maintaining barrier and highlight the HIF-1[alpha]/claudin-1 axis as a potential therapeutic target for EoE.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI126744