1. Inflammation-induced desmoglein-2 ectodomain shedding compromises the mucosal barrier
- Author
-
Dominique A. Weber, Mingli Feng, Charles A. Parkos, Porfirio Nava, Asma Nusrat, Miguel Quiros, Ryuta Kamekura, and Hikaru Nishio
- Subjects
Disintegrins ,CHO Cells ,Cell junction ,Cell Line ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,Cricetulus ,0302 clinical medicine ,Intestinal mucosa ,Cell Adhesion ,Disintegrin ,Animals ,Humans ,Intestinal Mucosa ,Desmosomal Cadherins ,Cell adhesion ,Molecular Biology ,030304 developmental biology ,Inflammation ,0303 health sciences ,Desmoglein 2 ,biology ,Cadherin ,Articles ,Cell Biology ,3. Good health ,Cell biology ,Mice, Inbred C57BL ,Matrix Metalloproteinase 9 ,Ectodomain ,Cell Biology of Disease ,030220 oncology & carcinogenesis ,biology.protein ,Cytokines ,Female - Abstract
Proinflammatory cytokines promote desmoglein-2 (Dsg2) ectodomain shedding in intestinal epithelial cells. Epithelial exposure to Dsg2 ectodomains compromises intercellular adhesion while also promoting proliferation. These findings identify mechanisms by which mucosal inflammation–induced cleavage of Dsg2 influences intestinal epithelial homeostasis., Desmosomal cadherins mediate intercellular adhesion and control epithelial homeostasis. Recent studies show that proteinases play an important role in the pathobiology of cancer by targeting epithelial intercellular junction proteins such as cadherins. Here we describe the proinflammatory cytokine-induced activation of matrix metalloproteinase 9 and a disintegrin and metalloproteinase domain–containing protein 10, which promote the shedding of desmosomal cadherin desmoglein-2 (Dsg2) ectodomains in intestinal epithelial cells. Epithelial exposure to Dsg2 ectodomains compromises intercellular adhesion by promoting the relocalization of endogenous Dsg2 and E-cadherin from the plasma membrane while also promoting proliferation by activation of human epidermal growth factor receptor 2/3 signaling. Cadherin ectodomains were detected in the inflamed intestinal mucosa of mice with colitis and patients with ulcerative colitis. Taken together, our findings reveal a novel response pathway in which inflammation-induced modification of columnar epithelial cell cadherins decreases intercellular adhesion while enhancing cellular proliferation, which may serve as a compensatory mechanism to promote repair.
- Published
- 2015