Epithelial HIF-1α/claudin-1 axis regulates barrier dysfunction in eosinophilic esophagitis

J Clin Invest. 2019 Jul 2;129(8):3224-3235. doi: 10.1172/JCI126744.


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.

Keywords: Allergy; Gastroenterology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Cell Line, Transformed
  • Child
  • Child, Preschool
  • Claudin-1 / genetics
  • Claudin-1 / metabolism*
  • Eosinophilic Esophagitis / genetics
  • Eosinophilic Esophagitis / metabolism*
  • Eosinophilic Esophagitis / pathology
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Female
  • Gene Expression Regulation
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Protein Stability
  • Signal Transduction*
  • Tight Junctions / genetics
  • Tight Junctions / metabolism*
  • Tight Junctions / pathology


  • CLDN1 protein, human
  • Claudin-1
  • Cldn1 protein, mouse
  • HIF1A protein, human
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit