title: Targeted colonic claudin-2 expression renders resistance to epithelial injury, induces immune suppression, and protects from colitis.
abstract: Expression of claudin-2, a tight junction protein, is highly upregulated during inflammatory bowel disease (IBD) and, due to its association with epithelial permeability, has been postulated to promote inflammation. Notably, claudin-2 has also been implicated in the regulation of intestinal epithelial proliferation. However, precise role of claudin-2 in regulating colonic homeostasis remains unclear. Here, we demonstrate, using Villin-Claudin-2 transgenic mice, that increased colonic claudin-2 expression augments mucosal permeability as well as colon and crypt length. Most notably, despite leaky colon, Cl-2TG mice were significantly protected against experimental colitis. Importantly, claudin-2 expression increased colonocyte proliferation and provided protection against colitis-induced colonocyte death in a PI-3Kinase/Bcl-2-dependent manner. However, Cl-2TG mice also demonstrated marked suppression of colitis-induced increases in immune activation and associated signaling, suggesting immune tolerance. Accordingly, colons from naive Cl-2TG mice harbored significantly increased numbers of regulatory (CD4(+)Foxp3(+)) T cells than WT littermates. Furthermore, macrophages isolated from Cl-2TG mouse colon exhibited immune anergy. Importantly, these immunosuppressive changes were associated with increased synthesis of the immunoregulatory cytokine TGF-β by colonic epithelial cells in Cl-2TG mice compared with WT littermates. Taken together, our findings reveal a critical albeit complex role of claudin-2 in intestinal homeostasis by regulating epithelial permeability, inflammation and proliferation and suggest novel therapeutic opportunities.
authors.affiliation: Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ahmad
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: R
authors.initials: R
authors.lastname: Chaturvedi
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: D
authors.initials: D
authors.lastname: Olivares-Villagómez
authors.affiliation: Badger Technical Services, Vicksburg, Mississippi, USA.
authors.forename: T
authors.initials: T
authors.lastname: Habib
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: M
authors.initials: M
authors.lastname: Asim
authors.affiliation: University of Southern California & Children's Hospital Los Angeles, Los Angeles, California, USA.
authors.forename: P
authors.initials: P
authors.lastname: Shivesh
authors.affiliation: University of Southern California & Children's Hospital Los Angeles, Los Angeles, California, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Polk
authors.affiliation: 1] Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA [2] Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA [3] Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: Wilson
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Washington
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: L
authors.initials: L
authors.lastname: Van Kaer
authors.affiliation: 1] Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee, USA [2] Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA [3] The Veterans Affair Medical Center, Nashville, Tennessee, USA.
authors.forename: P
authors.initials: P
authors.lastname: Dhawan
authors.affiliation: 1] Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee, USA [2] Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Singh
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D057167:Claudins / Q000235:genetics / Q000276:immunology*; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D007413:Intestinal Mucosa / Q000276:immunology* / Q000293:injuries / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
chemical_list: C491875:CLDN2 protein, human; D057167:Claudins; C113371:Cldn2 protein, mouse