Role of the desmosmal adhesion molecule desmoglein 2 in Crohn’s disease (60.4)

Abstract

The barrier function established by intestinal epithelial cells is essential for gut homeostasis and is compromised in inflammatory bowel disease (IBD). This function is dependent on junctional complexes comprising of a set of intercellular junctions, namely tight junctions, adherens junctions, and desmosomes. Previously, we have shown that intercellular adhesion mediated by the desmosomal adhesion molecule desmoglein2 (Dsg2) is required for the integrity of tight junctions. Here, we demonstrate that Dsg2 levels are dramatically reduced in biopsies of patients with Crohn’s disease. Furthermore TNFa, a central cytokine in IBD, led to loss of cell cohesion, reduced Dsg2 expression, and increased permeability in Caco‐2 and HCT116 cells. This was paralleled by loss of Dsg2 immunostaining at cell borders with concomitant reduction of the tight junction protein claudin1. These effects were mediated at least in part by increased activity of p38MAPK, since inhibition of this kinase restored intercellular adhesion and blunted the permeability increase induced by TNFa. Importantly, stabilizing desmosomal adhesion via a Dsg‐specific peptide ameliorated loss of barrier functions. Thus, our data indicate an important role of p38MAPK‐mediated regulation of desmosomal adhesion for epithelial permeability and suggest a contribution of reduced Dsg2 expression to the pathogenesis of Crohn’s disease.