Epithelial HIF-1α/claudin-1 axis regulates barrier dysfunction in eosinophilic esophagitis.
J Clin Invest
; 129(8): 3224-3235, 2019 07 02.
Article
em En
| MEDLINE
| ID: mdl-31264974
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
/
Junções Íntimas
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Células Epiteliais
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Subunidade alfa do Fator 1 Induzível por Hipóxia
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Esofagite Eosinofílica
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Claudina-1
Tipo de estudo:
Prognostic_studies
Limite:
Adolescent
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Adult
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Animals
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Child
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Child, preschool
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Female
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Humans
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Male
Idioma:
En
Revista:
J Clin Invest
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Irlanda