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.

项目概要免疫介导的远端小肠炎症或回肠炎是一种常见且令人衰弱的特征炎症性肠病、克罗恩病然而，控制局部免疫功能的机制。回肠炎症的定义仍然不明确，该提议探讨了一种新的途径。循环 CD4+ T 效应细胞 (Teff)——包括产生 IFNγ 的 Th1 细胞和分泌 IL-17A 的 Th17 细胞—— 补偿回肠中胆汁酸（BA）的细胞毒性浓度，以维护免疫稳态。长期以来被认为是简单的乳化剂，在肝脏和回肠之间消除，并促进膳食脂质的吸收和消除，BA现已成为多效性信号代谢物，通过与种系编码受体的动态相互作用来调节宿主代谢和炎症我们已经证明 Teff 细胞上调异生物质转运蛋白的表达， 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回肠炎我们还发现了局部重吸收的 BA 的存在。免疫细胞中功能未知的传感核受体——作为 MDR1 (Abcb1a) 基因的驱动因素 Teff 细胞中 MDR1 或 CAR 的缺失或敲除会导致严重的后果。从机制上讲，我们的数据表明 CAR 对免疫缺陷 Rag1-/- 小鼠有反应。通过激活多种药物加工酶的表达来抑制回肠中粘膜相关的 BA 粘膜 Teff 细胞中的转运蛋白（包括 MDR1）可以解毒 BA 并增强局部免疫稳态。该机制与克罗恩病的理解和治疗直接相关，例如：（i）MDR1 (ii) MDR1 功能丧失；在部分克罗恩病患者中很明显；(iii) 考来烯胺，一种 FDA 批准的胆汁酸螯合剂可阻止 BA 重吸收到回肠粘膜中，减轻 T 细胞转移和回肠炎此外，这种机制建立了一种意想不到的新机制。我们提出的研究使用遗传和药理学方法以及临床相关的克罗恩病小鼠模型，以确定 CAR 及其这些研究表明转录靶标与 BA 相互作用以增强回肠的免疫稳态。将揭示回肠局部免疫稳态的重要新途径，同时具有对于提高我们对人类克罗恩病的理解和治疗具有重要意义。