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

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 (DSG3). Moreover, DSG1 deficiency induces transcriptional changes that partially overlap with the transcriptome of inflamed esophageal mucosa; notably, periostin, 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 Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Author Manuscript 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 periostin. HHS Public Access

Synaptopodin is upregulated by IL-13 in eosinophilic esophagitis and regulates esophageal epithelial cell motility and barrier integrity

“…Most findings that underscore the critical role of IBF in pathogenesis of EoE have focused on structural epithelial proteins, such as DSG1, or proteases, such as CAPN14 (11,14,53). Our findings -that actin-associated proteins are significantly upregulated in EoE, correlate with EoE severity, and alter esophageal epithelial integrity in cultured cells -signify the potential involvement of SYNPO and other actin-binding proteins in the pathogenesis of EoE.…”

“…EoE pathogenesis is driven by IL-13-mediated transcriptional responses of the esophageal epithelium (7,8), which are collectively improved by steroids (9). Structural and transcriptional changes observed in the inflamed epithelium in biopsies from patients with EoE can be recapitulated in vitro by treating esophageal epithelial cells with IL-13 (10)(11)(12)(13). IL-13 is thought to mediate these responses through epigenetic changes, including elevated levels of histone acetylation and decreased DNA methylation in the promoters of critical mediators, such as eotaxin 3 (also known as CCL26), CAPN14, and NTRK1 (14)(15)(16).…”

Eosinophilic esophagitis is characterized by a non-IgE-mediated food hypersensitivity

“…Desmoglein (DSG)-1, an intercellular adhesion molecule responsible for epithelial integrity and barrier function was one of the most strongly downregulated genes in EoE (29). A downregulation of DSG-1 gene, for example, by IL-13, was shown to result in the separation of epithelial cells (spongiosis) followed by impaired barrier function as well as by periostin induction further potentiating inflammation (57). Ultrastructural analysis revealed a significantly decreased number of desmosomes per cell in EoE biopsies as compared to healthy controls, which was reversible after treatment (58).…”

Eosinophilic Esophagitis

“…1). Interleukin-13 has been shown to downregulate desmoglein-1 21 and filaggrin 22 in vitro. Altered epithelial permeability 23 can lead to a permissive environment that enhances antigen presentation, which in turn leads to recruitment of eosinophils.…”