Intestinal vitamin D receptor signaling ameliorates dextran sulfate sodium‐induced colitis by suppressing necroptosis of intestinal epithelial cells

Abstract

Vitamin D status is closely related to inflammatory bowel disease (IBD), but the mechanism has not been fully elucidated. This study explored the effect of intestinal vitamin D signaling on necroptosis and the underlying mechanism in colitis. Serum 25(OH)D levels and the expression of necroptotic proteins were examined in patients with IBD. Colitis was induced in an intestinal‐specific hVDR transgenic model, and the gross manifestation, histological integrity, and intestinal barrier function were tested. The findings were further confirmed in vitro. Immunoprecipitation and colocalization were performed to investigate the association between the vitamin D receptor and necroptotic proteins. We found that serum 25(OH)D decreased in patients with IBD, while the expression of necroptotic proteins increased. The intestinal hVDR transgenic model could largely ameliorate the structural destruction, restore barrier dysfunction, and suppress necroptosis caused by DSS. This was probably achieved by binding to RIPK1/3 necrosomes, as we observed decreased RIPK1/3 necrosome formation and increased VDR expression in the cytosol. This study demonstrated an inhibitory effect of the intestinal vitamin D signaling pathway on necroptosis in DSS‐induced colitis. The vitamin D receptor shifts from the nucleus to the cytosol to impede the formation of RIPK1/3. Our findings may offer some theoretical basis for a novel treatment of IBD in clinical practice.

Vitamin D receptor inhibits EMT via regulation of the epithelial mitochondrial function in intestinal fibrosis

“…In addition, mice with VDR knockout spontaneously develop hepatic fibrosis as a consequence of intersecting VDR/Smad genomic pathways (31). In acute enteritis, VDR maintains intestinal epithelial integrity by inhibiting apoptosis and necroptosis (32,33). Therefore, we investigated whether VDR functions in intestinal fibrosis induced by repeated inflammation.…”

RIP3 knockdown inhibits necroptosis of human intestinal epithelial cells via TLR4/MyD88/NF-κB signaling and ameliorates murine colitis

“…Does RIP3-mediated cell necroptosis play an important role in the pathogenesis of UC? Endogenous ligand/receptor signaling such as vitamin D/Vitamin D receptor (VDR) may inhibit RIP3-mediated necroptosis; Vitamin D and VDR signaling has been shown to have immune-protective effects on inflammatory bowel disease [ 41 ] and suppress necroptosis in intestinal epithelial cells by binding RIPK1/3 necrosomes [ 42 ]. In this study, we applied two RIP3 inhibitors—Nec-1 and GSK872.…”

Role of vitamin D3 on IL-17 expression in colon and improvement of colonic mucosa in an inflammatory bowel disease mice model

“…A study reported an inhibitory effect of the intestinal vitamin D signaling pathway on DSS-induced necroptosis colitis in IBD patients, 16 while another in-vitro experimental study reported that DSS-induced colonic mucosal damage was more severe in mice with vitamin D receptor (VDR) deletion of the colonic epithelium than in the control group. 17 Moreover, another study showed that vitamin D deficiency in experimental models caused colitis with clinical symptoms and severe colonic mucosal damage. 18 In our study, IL-17 expression in Group 2 (5% DSS alone) was significantly higher than in Group 1 (control), indicating that IL-17 expression increases in colitis conditions.…”