Bile acid-dependent T cell regulation in the intestine

肠道内胆汁酸依赖性 T 细胞调节

基本信息

批准号：
10591659
负责人：
Mark Scott Sundrud
金额：
$ 31.44万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-06 至 2022-09-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10591659
关键词：
ABCB1 gene ASBT protein ATAC-seq Attenuated Bile Acids CD4 Positive T Lymphocytes Cell physiology Cells Cholestyramine Chronic Crohn&apos s disease Data Dietary Fats Distal Emulsifying Agents Enzymes FDA approved Functional disorder Gene Expression Genes Genetic Genetic Transcription Helper-Inducer T-Lymphocyte Hepatotoxicity Homeostasis Human Ileitis Immune Immune system Inflammation Inflammatory Bowel Diseases Interferons Interleukin-17 Intestinal Mucosa Intestines Liver Mediating Metabolism Modeling Mucous Membrane Mus Nuclear Receptors Oxidative Stress Pathogenesis Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Pharmacology RNA interference screen Rag1 Mouse Receptor Activation Reporting Research Personnel Role Signal Transduction Small Intestines Supplementation T cell regulation T-Lymphocyte Testing Therapeutic Intervention Toxic effect Universities Up-Regulation Xenobiotics absorption clinically relevant constitutive androstane receptor cytokine cytotoxic effector T cell gut microbiota ileum immune function immunoregulation improved in vivo knock-down loss of function migration mouse model novel prevent receptor receptor function reconstitution reuptake therapeutic target tool transcriptome sequencing

项目摘要

Project Summary Immune-mediated inflammation of the distal small intestine, or ileitis, is a common and debilitating feature of the inflammatory bowel disease, Crohn’s disease. However, the mechanisms governing local immune function and inflammation in the ileum remain poorly defined. This proposal interrogates a novel pathway by which circulating CD4+ T effector (Teff) cells—including IFN-producing Th1 and IL-17A-secreting Th17 cells— compensate for cytotoxic concentrations of bile acids (BAs) in the ileum to safeguard immune homeostasis. Long considered simple emulsifying agents that circulate between the liver and ileum and that facilitate absorption and elimination of dietary lipids, BAs have now emerged as pleiotropic signaling metabolites that regulate host metabolism and inflammation via dynamic interactions with both germline-encoded receptors and the intestinal microbiota. We have shown that Teff cells upregulate expression of the xenobiotic transporter, MDR1, in the ileum to limit oxidative stress, prevent pathogenic cytokine secretion and suppress ileitis in the presence of locally-reabsorbed BAs. We have also identified the constitutive androstane receptor (CAR)–a BA- sensing nuclear receptor with no known function in immune cells—as a driver of MDR1 (Abcb1a) gene expression in mucosal Teff cells. Loss or knockdown of either MDR1 or CAR in Teff cells precipitates severe ileitis upon transfer into immunodeficient Rag1-/- mice. Mechanistically, our data suggest that CAR responds to mucosa-associated BAs in the ileum by activating the expression of numerous drug-processing enzymes and transporters in mucosal Teff cells, including MDR1, to detoxify BAs and enforce local immune homeostasis. This mechanism is directly relevant to the understanding and treatment of Crohn’s disease, as: (i) MDR1 expression in human Teff cells is increased markedly in the intestinal mucosa; (ii) MDR1 loss-of-function is evident in a subset of Crohn’s disease patients; and (iii) cholestyramine, an FDA-approved bile acid sequestrant that blocks BA reabsorption into the ileal mucosa, attenuates ileitis in both T cell transfer and spontaneous mouse models of Crohn’s disease. In addition, this mechanism establishes an unexpected new regulatory function of BAs. Our proposed studies use genetic and pharmacologic approaches, as well as clinically-relevant mouse models of Crohn’s disease, to define the mechanisms by which CAR and its transcriptional targets interact with BAs to enforce immune homeostasis in the ileum. Together, these studies will bring to light an important new pathway underlying local immune homeostasis in the ileum, whilst having important implications for improving our understanding and treatment of human Crohn’s disease.

项目摘要免疫介导的远端小肠或回肠炎的炎症是常见且令人衰弱的特征。炎症性肠病，克罗恩病。但是，管理局部免疫功能的机制回肠的炎症仍然很差。该提议询问了一条新颖的途径循环的CD4+ T效应子（TEFF）细胞 - 包括产生IFN的TH1和IL-17A分泌Th17细胞 - 补偿回肠中胆汁酸（BAS）的细胞毒性浓度，以保护免疫稳态。长期认为简单的乳化剂，这些剂量在肝脏和回肠之间圆圈，并有助于 BAS的吸收和消除饮食脂质现在已成为多效信号代谢物，通过与种系编码的受体和肠菌群。我们已经表明，teff细胞上调异种生物转运蛋白的表达， MDR1，在回肠中限制氧化应激，防止致病性细胞因子分泌并抑制肠炎存在局部刺激的BAS。我们还确定了组成型雄激素受体（CAR）–A BA- 在免疫细胞中感应没有已知功能的核接收器 - 作为MDR1（ABCB1A）基因的驱动器粘膜Teff细胞中的表达。 MDR1或TEFF电池中的CAR损失或敲除严重的回肠炎转移到免疫缺陷的RAG1 - / - 小鼠中。从机械上讲，我们的数据表明汽车对通过激活许多药物加工酶的表达和包括MDR1在内的粘膜TEFF细胞中的转运蛋白，以对BAS排毒并强制局部免疫稳态。该机制与对克罗恩病的理解和治疗直接相关，为：（i）MDR1 在肠粘膜中，人teff细胞中的表达显着增加。（ii）MDR1功能丧失是克罗恩病患者一部分的证据；（iii）胆碱胺，一种由FDA批准的胆汁酸阻塞BA重吸收到回肠粘膜中的隔离剂会减弱T细胞转移和克罗恩氏病的赞助小鼠模型。此外，这种机制确立了一个意想不到的新 BAS的调节功能。我们提出的研究使用遗传和药物方法，以及克罗恩病的临床相关小鼠模型，以定义汽车及其及其疾病的机制转录靶标与BAS相互作用，以在回肠中执行免疫稳态。在一起，这些研究将揭示出回肠局部免疫稳态的重要新途径，同时有改善我们对人类克罗恩病的理解和治疗的重要意义。