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Mucosal Immunol. 2014 May;7(3):718-29. doi: 10.1038/mi.2013.90. Epub 2013 Nov 13.

Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis.

Author information

1
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3026, USA.
2
Departments of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7545, USA.
3
Nutrition and Health Department, Nestlé Research Centre, 1000 Lausanne, Switzerland.
4
Divisions of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3026, USA.
5
Divisions of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3026, USA.
6
1] Departments of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7545, USA [2] Departments of Cell and Molecular Physiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7545, USA.

Abstract

The desmosomal cadherin desmoglein-1 (DSG1) is an essential intercellular adhesion molecule that is altered in various human cutaneous disorders; however, its regulation and function in allergic disease remains unexplored. Herein, we demonstrate a specific reduction in DSG1 in esophageal biopsies from patients with eosinophilic esophagitis (EoE), an emerging allergic disorder characterized by chronic inflammation within the esophageal mucosa. Further, we show that DSG1 gene silencing weakens esophageal epithelial integrity, and induces cell separation and impaired barrier function (IBF) despite high levels of desmoglein-3. Moreover, DSG1 deficiency induces transcriptional changes that partially overlap with the transcriptome of inflamed esophageal mucosa; notably, periostin (POSTN), a multipotent pro-inflammatory extracellular matrix molecule, is the top induced overlapping gene. We further demonstrate that IBF is a pathological feature in EoE, which can be partially induced through the downregulation of DSG1 by interleukin-13 (IL-13). Taken together, these data identify a functional role for DSG1 and its dysregulation by IL-13 in the pathophysiology of EoE and suggest that the loss of DSG1 may potentiate allergic inflammation through the induction of pro-inflammatory mediators such as POSTN.

PMID:
24220297
PMCID:
PMC3999291
DOI:
10.1038/mi.2013.90
[Indexed for MEDLINE]
Free PMC Article

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