Loss of Desmoglein 2 Contributes to the Pathogenesis of Crohn's Disease.
Spindler, Volker MD *; Meir, Michael MD +; Vigh, Balazs MD *; Flemming, Sven MD +; Hutz, Katharina PhD *; Germer, Christoph-Thomas MD +; Waschke, Jens MD *; Schlegel, Nicolas MD +
Inflammatory Bowel Diseases.
21(10):2349-2359, October 2015.
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Background: The intestinal epithelium of patients with Crohn's disease (CD) is characterized by defects in permeability and alterations in tight junction morphology sealing the paracellular cleft. Desmosomes are primarily considered to mediate strong intercellular cohesion. Because barrier properties of epithelial cells were shown to depend on the function of the desmosomal adhesion molecule desmoglein 2 (Dsg2), we here investigated the relevance of Dsg2 for CD.
Methods: Biopsies from the terminal ileum of 14 patients with CD and 12 healthy controls were investigated for changes in cell adhesion molecules. Two intestinal epithelial cell lines were used for functional studies. A tandem peptide modulating Dsg binding was applied to strengthen Dsg2 interaction.
Results: Dsg2 but not the adherens junction molecule E-cadherin was strongly reduced in the mucosa of patients with CD. TNF-[alpha], a central cytokine in CD pathogenesis, led to loss of cell cohesion and increased permeability in cultured epithelial cells, which was paralleled by loss of Dsg2 at cell borders, reduction of the tight junction component claudin-1, and upregulation of claudin-2. These effects were mediated at least in part by increased activity of p38MAPK because inhibition of this kinase restored intercellular adhesion and blunted the permeability increase induced by TNF-[alpha]. Importantly, stabilizing desmosomal adhesion through tandem peptide ameliorated loss of barrier functions and prevented claudin-2 increase.
Conclusions: We show an important role of p38MAPK-mediated regulation of desmosomal adhesion resulting in upregulation of claudin-2 in CD. Our data suggest peptide-mediated strengthening of impaired Dsg2 adhesion as a novel therapeutic approach in CD.
(C) Crohn's & Colitis Foundation of America, Inc.