Targeted colonic claudin-2 expression renders resistance to epithelial injury, induces immune suppression, and protects from colitis

R. Ahmad, R. Chaturvedi, D. Olivares-Villagómez, T. Habib, M. Asim, P. Shivesh, D. B. Polk, K. T. Wilson, M. K. Washington, L. Van Kaer, P. Dhawan, A. B. Singh

Research output: Contribution to journalArticle

58 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1340-1353
Number of pages14
JournalMucosal Immunology
Volume7
Issue number6
DOIs
StatePublished - Nov 25 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Ahmad, R., Chaturvedi, R., Olivares-Villagómez, D., Habib, T., Asim, M., Shivesh, P., Polk, D. B., Wilson, K. T., Washington, M. K., Van Kaer, L., Dhawan, P., & Singh, A. B. (2014). Targeted colonic claudin-2 expression renders resistance to epithelial injury, induces immune suppression, and protects from colitis. Mucosal Immunology, 7(6), 1340-1353. https://doi.org/10.1038/mi.2014.21