Masterson, Joanne C. and Biette, K.A. and Hammer, J.A. and Nguyen, Nathalie and Capocelli, Kelley E. and Saeedi, Bejan J. and Harris, Rachel F. and Fernando, Shahan D. and Hosford, Lindsay and Kelly, Caleb J. and Campbell, Eric L. and Ehrentraut, Stefan F. and Ahmed, Faria N. and Nakagawa, Hiroshi and Lee, James J. and McNamee, Eóin N. and Glover, Louise and Colgan, S.P. and Furuta, Glenn T. (2019) Epithelial HIF-1α/claudin-1 axis regulates barrier dysfunction in eosinophilic esophagitis. The Journal of Clinical Investigation, 129 (8). pp. 3224-3235. ISSN 0021-9738

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Abstract

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-1α orchestrated epithelial barrier integrity, selectively controlling tight junction CLDN1 (claudin-1). Prolonged experimental hypoxia or HIF1A knockdown suppressed HIF-1α– dependent claudin-1 expression and epithelial barrier function, as documented in 3D organotypic epithelial cultures. L2-IL5OXA mice with EoE-relevant allergic inflammation displayed localized eosinophil oxygen metabolism, tissue hypoxia, and impaired claudin-1 barrier via repression of HIF-1α/claudin-1 signaling, which was restored by transgenic expression of esophageal epithelial-targeted stabilized HIF-1α. EoE patient biopsy analysis identified a repressed HIF-1α/claudin-1 axis, which was restored via pharmacologic HIF-1α stabilization ex vivo. Collectively, these studies reveal HIF-1α’s critical role in maintaining barrier and highlight the HIF-1α/claudin-1 axis as a potential therapeutic target for EoE.

Item Type:	Article
Additional Information:	This is the postprint version of the published article, which is available at J Clin Invest. 2019;129(8):3224-3235. https://doi.org/10.1172/JCI126744.
Keywords:	Epithelial; HIF-1α; claudin-1 axis; regulates; barrier; dysfunction; eosinophilic esophagitis;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	13998
Identification Number:	https://doi.org/10.1172/JCI126744
Depositing User:	Joanne Masterson
Date Deposited:	12 Feb 2021 10:58
Journal or Publication Title:	The Journal of Clinical Investigation
Publisher:	American Society for Clinical Investigation
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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