Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
Department of Medicine, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, United Kingdom.
Gastroenterology. 2021 Mar;160(4):1269-1283. doi: 10.1053/j.gastro.2020.11.015. Epub 2020 Nov 18.
Vitamin D exerts a regulatory role over mucosal immunity via the vitamin D receptor (VDR). Although Paneth cells and their products are known to regulate the commensal and pathogenic microbiota, the role that VDRs in Paneth cells play in these responses is unknown.
We identified the decreased intestinal VDR significantly correlated with reduction of an inflammatory bowel disease risk gene ATG16L1 and Paneth cell lysozymes in patients with Crohn's disease. We generated Paneth cell-specific VDR knockout (VDR) mice to investigate the molecular mechanisms.
Lysozymes in the Paneth cells were significantly decreased in the VDR mice. Isolated VDR Paneth cells exhibited weakened inhibition of pathogenic bacterial growth and displayed reduced autophagic responses. VDR mice had significantly higher inflammation after Salmonella infections. VDR mice also showed high susceptibility to small intestinal injury induced by indomethacin, a nonsteroidal anti-inflammatory drug. Co-housing of VDR and VDR mice made the VDR less vulnerable to dextran sulfate sodium colitis, suggesting the transmission of protective bacterial from the VDR mice. Thus, a lack of VDR in Paneth cells leads to impaired antibacterial activities and consequently increased inflammatory responses. Genetically and environmentally regulated VDRs in the Paneth cells may set the threshold for the development of chronic inflammation, as observed in inflammatory bowel diseases.
We provide new insights into the tissue-specific functions of VDRs in maintaining Paneth cell alertness to pathogens in intestinal disorders. Targeting the VDR affects multiple downstream events within Paneth cells that inhibit intestinal inflammation and establish host defense against enteropathogens.
维生素 D 通过维生素 D 受体（VDR）对黏膜免疫发挥调节作用。虽然已知潘氏细胞及其产物可调节共生菌和致病菌菌群，但 VDR 在潘氏细胞中在这些反应中的作用尚不清楚。
我们发现，克罗恩病患者的肠道 VDR 减少与炎症性肠病风险基因 ATG16L1 和潘氏细胞溶菌酶的减少显著相关。我们生成了潘氏细胞特异性 VDR 敲除（VDR）小鼠，以研究分子机制。
VDR 小鼠的潘氏细胞溶菌酶显著减少。分离的 VDR 潘氏细胞表现出对致病性细菌生长的抑制作用减弱，自噬反应减少。沙门氏菌感染后，VDR 小鼠的炎症明显增加。VDR 小鼠也表现出对非甾体抗炎药吲哚美辛诱导的小肠损伤的高易感性。VDR 和 VDR 小鼠共同饲养使 VDR 对葡聚糖硫酸钠结肠炎的易感性降低，表明 VDR 小鼠中保护性细菌的传递。因此，潘氏细胞中缺乏 VDR 会导致抗菌活性受损，进而导致炎症反应增加。潘氏细胞中遗传和环境调节的 VDR 可能为炎症性肠病中观察到的慢性炎症的发展设定了阈值。
我们提供了新的见解，即 VDR 在维持肠道疾病中潘氏细胞对病原体的警惕性方面具有组织特异性功能。靶向 VDR 会影响潘氏细胞内的多个下游事件，抑制肠道炎症并建立宿主对肠道病原体的防御。
