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Epithelial HIF-1α/claudin-1 axis regulates barrier dysfunction in eosinophilic esophagitis.
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, Eóin N; Glover, Louise E; Colgan, Sean P; Furuta, Glenn T.
Afiliación
  • Masterson JC; Allergy, Inflammation and Remodeling Research Laboratory, Human Health Research Institute, Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland.
  • Biette KA; Gastrointestinal Eosinophilic Diseases Program, Department of Pediatrics, University of Colorado School of Medicine; Digestive Health Institute, Children's Hospital Colorado; Aurora, Colorado, USA.
  • Hammer JA; Mucosal Inflammation Program, Department of Medicine, University of Colorado, Aurora, Colorado, USA.
  • Nguyen N; Gastrointestinal Eosinophilic Diseases Program, Department of Pediatrics, University of Colorado School of Medicine; Digestive Health Institute, Children's Hospital Colorado; Aurora, Colorado, USA.
  • Capocelli KE; Mucosal Inflammation Program, Department of Medicine, University of Colorado, Aurora, Colorado, USA.
  • Saeedi BJ; Gastrointestinal Eosinophilic Diseases Program, Department of Pediatrics, University of Colorado School of Medicine; Digestive Health Institute, Children's Hospital Colorado; Aurora, Colorado, USA.
  • Harris RF; Mucosal Inflammation Program, Department of Medicine, University of Colorado, Aurora, Colorado, USA.
  • Fernando SD; Gastrointestinal Eosinophilic Diseases Program, Department of Pediatrics, University of Colorado School of Medicine; Digestive Health Institute, Children's Hospital Colorado; Aurora, Colorado, USA.
  • Hosford LB; Mucosal Inflammation Program, Department of Medicine, University of Colorado, Aurora, Colorado, USA.
  • Kelly CJ; Department of Pathology, Children's Hospital Colorado, Aurora, Colorado, USA.
  • Campbell EL; Mucosal Inflammation Program, Department of Medicine, University of Colorado, Aurora, Colorado, USA.
  • Ehrentraut SF; Gastrointestinal Eosinophilic Diseases Program, Department of Pediatrics, University of Colorado School of Medicine; Digestive Health Institute, Children's Hospital Colorado; Aurora, Colorado, USA.
  • Ahmed FN; Mucosal Inflammation Program, Department of Medicine, University of Colorado, Aurora, Colorado, USA.
  • Nakagawa H; Gastrointestinal Eosinophilic Diseases Program, Department of Pediatrics, University of Colorado School of Medicine; Digestive Health Institute, Children's Hospital Colorado; Aurora, Colorado, USA.
  • Lee JJ; Mucosal Inflammation Program, Department of Medicine, University of Colorado, Aurora, Colorado, USA.
  • McNamee EN; Gastrointestinal Eosinophilic Diseases Program, Department of Pediatrics, University of Colorado School of Medicine; Digestive Health Institute, Children's Hospital Colorado; Aurora, Colorado, USA.
  • Glover LE; Mucosal Inflammation Program, Department of Medicine, University of Colorado, Aurora, Colorado, USA.
  • Colgan SP; Mucosal Inflammation Program, Department of Medicine, University of Colorado, Aurora, Colorado, USA.
  • Furuta GT; Mucosal Inflammation Program, Department of Medicine, University of Colorado, Aurora, Colorado, USA.
J Clin Invest ; 129(8): 3224-3235, 2019 07 02.
Article en En | MEDLINE | ID: mdl-31264974
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Uniones Estrechas / Células Epiteliales / Subunidad alfa del Factor 1 Inducible por Hipoxia / Esofagitis Eosinofílica / Claudina-1 Tipo de estudio: Prognostic_studies Límite: Adolescent / Adult / Animals / Child / Child, preschool / Female / Humans / Male Idioma: En Revista: J Clin Invest Año: 2019 Tipo del documento: Article País de afiliación: Irlanda Pais de publicación: Estados Unidos
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Uniones Estrechas / Células Epiteliales / Subunidad alfa del Factor 1 Inducible por Hipoxia / Esofagitis Eosinofílica / Claudina-1 Tipo de estudio: Prognostic_studies Límite: Adolescent / Adult / Animals / Child / Child, preschool / Female / Humans / Male Idioma: En Revista: J Clin Invest Año: 2019 Tipo del documento: Article País de afiliación: Irlanda Pais de publicación: Estados Unidos