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Gross, Annika; Pack, Lotta A. P.; Schacht, Gabriel M.; Kant, Sebastian; Ungewiss, Hanna; Meir, Michael; Schlegel, Nicolas; Preisinger, Christian; Boor, Peter; Guldiken, Nurdan; Krusche, Claudia A.; Sellge, Gernot; Trautwein, Christian; Waschke, Jens; Heuser, Arnd; Leube, Rudolf E.; Strnad, Pavel (2018): Desmoglein 2, but not desmocollin 2, protects intestinal epithelia from injury. In: Mucosal Immunology, Vol. 11, No. 6: pp. 1630-1639
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Abstract

Desmosomes are the least understood intercellular junctions in the intestinal epithelia and provide cell-cell adhesion via the cadherins desmoglein (Dsg) 2 and desmocollin (Dsc) 2. We studied these cadherins in Crohn's disease (CD) patients and in newly generated conditional villin-Cre DSG2 and DSC2 knockout mice (DSG2(Delta IEC);DSC2(Delta IEC)). CD patients exhibited altered desmosomes and reduced Dsg2/Dsc2 levels. The intestines of both transgenic animal lines were histopathologically inconspicuous. However, DSG2(Delta IEC), but not DSC2(Delta IEC) mice displayed an increased intestinal permeability, a wider desmosomal space as well as alterations in desmosomal and tight junction components. After dextran sodium sulfate (DSS) treatment and Citrobacter rodentium exposure, DSG2(Delta IEC) mice developed a more-pronounced colitis, an enhanced intestinal epithelial barrier disruption, leading to a stronger inflammation and activation of epithelial pSTAT3 signaling. No susceptibility to DSS-induced intestinal injury was noted in DSC2(Delta IEC) animals. Dsg2 interacted with the cytoprotective chaperone Hsp70. Accordingly, DSG2(Delta IEC) mice had lower Hsp70 levels in the plasma membrane compartment, whereas DSC2(Delta IEC) mice displayed a compensatory recruitment of galectin 3, a junction-tightening protein. Our results demonstrate that Dsg2, but not Dsc2 is required for the integrity of the intestinal epithelial barrier in vivo.