CAR directs T cell adaptation to bile acids in the small intestine.
CAR directs T cell adaptation to bile acids in the small intestine.
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DOI：
10.1038/s41586-021-03421-6
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发表时间：
2021-05
期刊：
影响因子：
64.8
通讯作者：
Sundrud MS
中科院分区：
文献类型：
--
作者：
Chen ML;Huang X;Wang H;Hegner C;Liu Y;Shang J;Eliason A;Diao H;Park H;Frey B;Wang G;Mosure SA;Solt LA;Kojetin DJ;Rodriguez-Palacios A;Schady DA;Weaver CT;Pipkin ME;Moore DD;Sundrud MS
胆汁酸是肝细胞合成的脂乳化代谢产物，通过肝脏和小肠之间的肝-肠循环在体内维持。作为洗涤剂，胆汁酸会对肝组织造成毒性和炎症。核受体在肝细胞和肠细胞中维持胆汁酸的稳态，但目前尚不清楚粘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效应器(Tef)细胞上调异种转运蛋白MDR1(由Abcb1a编码)在Silp中的表达，以防止胆汁酸毒性和抑制克罗恩病样小肠炎症。在这里，我们发现异种核受体CAR(由Nr1I3编码)是T细胞MDR1表达的调节因子，可以保护小鼠小肠免受胆汁酸毒性和炎症。CAR的激活诱导了TJeff细胞的大规模转录重编程，这些细胞渗透到Silp，但不是结肠。CAR不仅诱导肝细胞解毒酶和转运蛋白的表达，而且还诱导关键的抗炎细胞因子IL-10的表达。因此，在T细胞重组的RAG1−/−或RAG2−/−小鼠中，T细胞中CAR缺乏加重胆汁酸驱动的回肠炎，而CAR的药物激活则抑制它。这些数据表明，CAR局部作用于T细胞，T细胞渗透到小肠中，以解毒胆汁酸和化解炎症。这一计划的激活为治疗小肠克罗恩病提供了一种意想不到的策略，并定义了小肠中的淋巴细胞亚特化。
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 (Teff) 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 Teff cells that infiltrated the siLP, but not the colon. CAR induced the expression of not only detoxifying enzymes and transporters in siLP Teff 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.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
DOI：
10.1016/j.bbagrm.2016.04.010
发表时间：
2016-09
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Cui JY;Klaassen CD
通讯作者：
Klaassen CD
影响因子：
14.9
作者：
Niu, Ben;Coslo, Denise M.;Omiecinski, Curtis J.
通讯作者：
Omiecinski, Curtis J.
影响因子：
6.5
作者：
LUDESCHER, C;THALER, J;HOFMANN, J
通讯作者：
HOFMANN, J
影响因子：
82.9
作者：
Gagliani, Nicola;Magnani, Chiara F.;Roncarolo, Maria-Grazia
通讯作者：
Roncarolo, Maria-Grazia