Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, P.R. China.
Department of Pediatrics, The Fourth Affiliated Hospital of China Medical University, Shenyang, P.R. China.
FASEB J. 2020 Oct;34(10):13494-13506. doi: 10.1096/fj.202000143RRR. Epub 2020 Aug 11.
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.
维生素 D 状态与炎症性肠病（IBD）密切相关，但机制尚未完全阐明。本研究探讨了肠道维生素 D 信号对结肠炎中坏死性凋亡的影响及其潜在机制。检测了 IBD 患者的血清 25(OH)D 水平和坏死性凋亡蛋白的表达。在肠道特异性 hVDR 转基因模型中诱导结肠炎，并测试了大体表现、组织学完整性和肠道屏障功能。在体外进一步证实了这些发现。进行免疫沉淀和共定位以研究维生素 D 受体与坏死性凋亡蛋白之间的关联。我们发现，IBD 患者的血清 25(OH)D 降低，而坏死性凋亡蛋白的表达增加。肠道 hVDR 转基因模型可以在很大程度上改善结构破坏，恢复屏障功能，并抑制 DSS 引起的坏死性凋亡。这可能是通过与 RIPK1/3 坏死小体结合实现的，因为我们观察到 RIPK1/3 坏死小体形成减少和细胞质中 VDR 表达增加。本研究表明，肠道维生素 D 信号通路对 DSS 诱导的结肠炎中的坏死性凋亡具有抑制作用。维生素 D 受体从细胞核转移到细胞质，以阻止 RIPK1/3 的形成。我们的发现可能为临床实践中 IBD 的新型治疗提供一些理论依据。
