Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA.
The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, USA.
Nature. 2021 May;593(7857):147-151. doi: 10.1038/s41586-021-03421-6. Epub 2021 Apr 7.
Bile acids are lipid-emulsifying metabolites synthesized in hepatocytes and maintained in vivo through enterohepatic circulation between the liver and small intestine. As detergents, bile acids can cause toxicity and inflammation in enterohepatic tissues. Nuclear receptors maintain bile acid homeostasis in hepatocytes and enterocytes, but it is unclear how mucosal immune cells tolerate high concentrations of bile acids in the small intestine lamina propria (siLP). CD4 T effector (T) cells upregulate expression of the xenobiotic transporter MDR1 (encoded by Abcb1a) in the siLP to prevent bile acid toxicity and suppress Crohn's disease-like small bowel inflammation. Here we identify the nuclear xenobiotic receptor CAR (encoded by Nr1i3) as a regulator of MDR1 expression in T cells that can safeguard against bile acid toxicity and inflammation in the mouse small intestine. Activation of CAR induced large-scale transcriptional reprogramming in T cells that infiltrated the siLP, but not the colon. CAR induced the expression of not only detoxifying enzymes and transporters in siLP T cells, as in hepatocytes, but also the key anti-inflammatory cytokine IL-10. Accordingly, CAR deficiency in T cells exacerbated bile acid-driven ileitis in T cell-reconstituted Rag1 or Rag2 mice, whereas pharmacological activation of CAR suppressed it. These data suggest that CAR acts locally in T cells that infiltrate the small intestine to detoxify bile acids and resolve inflammation. Activation of this program offers an unexpected strategy to treat small bowel Crohn's disease and defines lymphocyte sub-specialization in the small intestine.
胆汁酸是在肝细胞中合成的脂质乳化代谢物，并通过肝脏和小肠之间的肠肝循环在体内维持。作为去污剂，胆汁酸可导致肠肝组织毒性和炎症。核受体在肝细胞和肠细胞中维持胆汁酸的动态平衡，但尚不清楚黏膜免疫细胞如何耐受小肠固有层（siLP）中高浓度的胆汁酸。CD4 T 效应（T）细胞在上皮内上调异生物质转运蛋白 MDR1（由 Abcb1a 编码）的表达，以防止胆汁酸毒性并抑制类似克罗恩病的小肠炎症。在这里，我们确定核异生物质受体 CAR（由 Nr1i3 编码）为 T 细胞中 MDR1 表达的调节剂，可保护小鼠小肠免受胆汁酸毒性和炎症的影响。CAR 的激活诱导了浸润 siLP 的 T 细胞的大规模转录重编程，但不诱导结肠中的 T 细胞。CAR 不仅诱导了 siLP T 细胞中的解毒酶和转运蛋白的表达，如在肝细胞中，而且还诱导了关键的抗炎细胞因子 IL-10 的表达。因此，CAR 在 T 细胞中的缺乏加剧了 T 细胞再构成 Rag1 或 Rag2 小鼠中的胆汁酸驱动的回肠炎，而 CAR 的药理学激活则抑制了该过程。这些数据表明，CAR 在浸润小肠的 T 细胞中发挥局部作用，以解毒胆汁酸并解决炎症。激活该程序为治疗小肠克罗恩病提供了一个意外的策略，并定义了小肠中淋巴细胞的亚专业化。
