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

Area of Science:

• Cell Biology
• Immunology
• Gastroenterology

Background:

• Epithelial barrier dysfunction is implicated in allergic diseases such as eosinophilic esophagitis (EoE).
• Tissue hypoxia and increased metabolic demands in allergic inflammation can compromise barrier function.
• The precise mechanisms linking hypoxia to barrier integrity in allergy remain incompletely understood.

Purpose of the Study:

• To investigate the role of the oxygen-sensing transcription factor HIF-1α in regulating epithelial barrier integrity in the context of allergic inflammation.
• To identify the specific molecular targets regulated by HIF-1α that are critical for barrier function.
• To explore the therapeutic potential of targeting the HIF-1α pathway in EoE.

Main Methods:

• Utilized 3D organotypic epithelial cultures to model experimental hypoxia and HIF1A knockdown.
• Employed L2-IL5OXA mouse models of EoE-relevant allergic inflammation.
• Analyzed patient biopsies from EoE individuals and performed ex vivo pharmacologic HIF-1α stabilization.

Main Results:

• Hypoxia and HIF1A knockdown suppressed HIF-1α-dependent claudin-1 expression and impaired epithelial barrier function in vitro.
• EoE mouse models exhibited tissue hypoxia, eosinophil oxygen metabolism, and reduced claudin-1 expression, linked to repressed HIF-1α/claudin-1 signaling.
• Transgenic stabilization of HIF-1α in esophageal epithelium restored barrier function in mice.
• EoE patient biopsies showed a repressed HIF-1α/claudin-1 axis, which was successfully restored by pharmacologic HIF-1α stabilization ex vivo.

Conclusions:

• HIF-1α is a critical regulator of epithelial barrier integrity, selectively controlling claudin-1 expression.
• The HIF-1α/claudin-1 axis is repressed in EoE, contributing to barrier dysfunction.
• Targeting and stabilizing HIF-1α represents a promising therapeutic strategy for EoE and potentially other allergic barrier diseases.