Ishita Chatterjee1, Yongguo Zhang1, Jilei Zhang1, Rong Lu1, Yinglin Xia1, Jun Sun1,2,3,4. 1. Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA. 2. UIC Cancer Center, University of Illinois at Chicago, Chicago, IL, USA. 3. Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, USA. 4. Jesse Brown VA Medical Center, Chicago, IL, USA.
Abstract
BACKGROUND AND AIMS: Dysfunction of the vitamin D receptor [VDR] contributes to the aetiology of IBD by regulating autophagy, immune response, and mucosal permeability. VDR directly controls the paracellular tight junction protein Claudin-2. Claudin-2 and Claudin-15 are unique in maintaining paracellular permeability. Interestingly, claudin-15 mRNA was downregulated in patients with ulcerative colitis. However, the exact mechanism of Claudin-15 regulation in colitis is still unknown. Here, we investigated the protective role of VDR against intestinal inflammation via upregulating Claudin-15. METHODS: We analysed the correlation of Claudin-15 with the reduction of VDR in human colitis. We generated intestinal epithelial overexpression of VDR [O-VDR] mice to study the gain of function of VDR in colitis. Intestinal epithelial VDR knockout [VDR∆IEC] mice were used for the loss of function study. Colonoids and SKCO15 cells were used as in vitro models. RESULTS: Reduced Claudin-15 was significantly correlated with decreased VDR along the colonic epithelium of human IBD. O-VDR mice showed decreased susceptibility to chemically and bacterially induced colitis and marked increased Claudin-15 expression [both mRNA and protein] in the colon. Correspondingly, colonic Claudin-15 was reduced in VDR∆IEC mice, which were susceptible to colitis. Overexpression of intestinal epithelial VDR and vitamin D treatment resulted in a significantly increased Claudin-15. ChIP assays identified the direct binding of VDR to the claudin-15 promoter, suggesting that claudin-15 is a target gene of VDR. CONCLUSION: We demonstrated the mechanism of VDR upregulation of Claudin-15 to protect against colitis. This might enlighten the mechanism of barrier dysfunction in IBD and potential therapeutic strategies to inhibit inflammation. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation (ECCO) 2021.
BACKGROUND AND AIMS: Dysfunction of the vitamin D receptor [VDR] contributes to the aetiology of IBD by regulating autophagy, immune response, and mucosal permeability. VDR directly controls the paracellular tight junction protein Claudin-2. Claudin-2 and Claudin-15 are unique in maintaining paracellular permeability. Interestingly, claudin-15 mRNA was downregulated in patients with ulcerative colitis. However, the exact mechanism of Claudin-15 regulation in colitis is still unknown. Here, we investigated the protective role of VDR against intestinal inflammation via upregulating Claudin-15. METHODS: We analysed the correlation of Claudin-15 with the reduction of VDR in human colitis. We generated intestinal epithelial overexpression of VDR [O-VDR] mice to study the gain of function of VDR in colitis. Intestinal epithelial VDR knockout [VDR∆IEC] mice were used for the loss of function study. Colonoids and SKCO15 cells were used as in vitro models. RESULTS: Reduced Claudin-15 was significantly correlated with decreased VDR along the colonic epithelium of human IBD. O-VDR mice showed decreased susceptibility to chemically and bacterially induced colitis and marked increased Claudin-15 expression [both mRNA and protein] in the colon. Correspondingly, colonic Claudin-15 was reduced in VDR∆IEC mice, which were susceptible to colitis. Overexpression of intestinal epithelial VDR and vitamin D treatment resulted in a significantly increased Claudin-15. ChIP assays identified the direct binding of VDR to the claudin-15 promoter, suggesting that claudin-15 is a target gene of VDR. CONCLUSION: We demonstrated the mechanism of VDR upregulation of Claudin-15 to protect against colitis. This might enlighten the mechanism of barrier dysfunction in IBD and potential therapeutic strategies to inhibit inflammation. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation (ECCO) 2021.
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