title: Inflammation-induced desmoglein-2 ectodomain shedding compromises the mucosal barrier.
abstract: 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.
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322 Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 0608556, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Kamekura
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322 Department of Physiology, Biophysics, and Neuroscience, Center for Research and Advanced Studies, Mexico DF 07360, Mexico.
authors.forename: Porfirio
authors.initials: P
authors.lastname: Nava
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322 Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Mingli
authors.initials: M
authors.lastname: Feng
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322 Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Miguel
authors.initials: M
authors.lastname: Quiros
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Nishio
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322.
authors.forename: Dominique A
authors.initials: DA
authors.lastname: Weber
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322 Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Parkos
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322 Department of Pathology, University of Michigan, Ann Arbor, MI 48109 anusrat@umich.edu.
authors.forename: Asma
authors.initials: A
authors.lastname: Nusrat
mesh_terms: D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D003412:Cricetulus; D016207:Cytokines / Q000378:metabolism; D051301:Desmoglein 2 / Q000378:metabolism*; D019483:Disintegrins / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D016207:Cytokines; D051301:Desmoglein 2; D019483:Disintegrins; D020780:Matrix Metalloproteinase 9