Overexpression of Vitamin D Receptor in Intestinal Epithelia Protects Against Colitis via Upregulating Tight Junction Protein Claudin 15.

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.

• Authors: Ishita Chatterjee, Yongguo Zhang, Jilei Zhang, Rong Lu, Yinglin Xia, Jun Sun
• Journal: Journal of Crohn's & colitis (J Crohns Colitis) Vol. 15 Issue 10 Pg. 1720-1736 (10 07 2021) ISSN: 1876-4479 [Electronic] England
• PMID: 33690841 (Publication Type: Journal Article)
• Copyright: Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation (ECCO) 2021.

Chemical References

• Claudins
• RNA, Messenger
• Receptors, Calcitriol
• claudin 15

Topics

• Aged
• Animals
• Claudins (genetics, metabolism)
• Colitis (prevention & control)
• Colon (metabolism)
• Female
• Humans
• Intestinal Mucosa (metabolism)
• Male
• Mice, Knockout
• Middle Aged
• RNA, Messenger (metabolism)
• Receptors, Calcitriol (metabolism)
• Up-Regulation