Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis.
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.
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3026, USA.
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JD
Sherrill
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3026, USA.
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Kc
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3026, USA.
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Wu
Departments of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7545, USA.
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Djukic
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3026, USA.
J M
JM
Caldwell
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3026, USA.
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Stucke
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3026, USA.
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KA
Kemme
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3026, USA.
M S
MS
Costello
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3026, USA.
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Mingler
Nutrition and Health Department, Nestlé Research Centre, 1000 Lausanne, Switzerland.
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Blanchard
Divisions of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3026, USA.
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MH
Collins
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3026, USA.
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JP
Abonia
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.
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PE
Putnam
Departments of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7545, USA.
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ES
Dellon
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.
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Orlando
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3026, USA.
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Hogan
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3026, USA.
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ME
Rothenberg
D002454:Cell Differentiation / Q000235:genetics; D016000:Cluster Analysis; D051183:Desmoglein 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D057765:Eosinophilic Esophagitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007150:Immunohistochemistry; D018793:Interleukin-13 / Q000378:metabolism; D008954:Models, Biological; D009092:Mucous Membrane / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic
D051183:Desmoglein 1; D018793:Interleukin-13