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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：
10767546
负责人：
Mark Scott Sundrud
金额：
$ 38.67万
依托单位：
DARTMOUTH-HITCHCOCK CLINIC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-24 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10767546
关键词：
ABCB1 gene ASBT protein ATAC-seq Ablation Attenuated Bile Acids CD4 Positive T Lymphocytes Cell physiology Cells Cholestyramine Chronic Compensation Crohn&apos s disease Data Dietary Fats Distal Drug Metabolic Detoxication Emulsifying Agents Enzymes FDA approved Functional disorder Gene Expression Genes Genetic Genetic Transcription Helper-Inducer T-Lymphocyte Hepatotoxicity Homeostasis Human IL17 gene Ileitis Immune Immune system Immunologic Deficiency Syndromes Inflammation Inflammatory Bowel Diseases Intestinal Mucosa Intestines Liver Mediating Metabolism Modeling Mucous Membrane Mus Nuclear Receptors Oxidative Stress Pathogenesis Pathogenicity Pathway interactions Patients Pharmaceutical Preparations 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 pharmacologic 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炎症，或回肠炎，是一种常见的和衰弱的特点，炎症性肠病克罗恩病然而，控制局部免疫功能的机制并且回肠中的炎症仍然不清楚。这一提议提出了一条新的途径，循环CD 4 + T效应细胞（Teff）-包括产生IFN γ的Th 1和分泌IL-17 A的Th 17细胞- 补偿回肠中胆汁酸（BA）的细胞毒性浓度，以保护免疫稳态。长期以来被认为是简单的乳化剂，在肝脏和回肠之间循环，由于膳食脂质的吸收和消除，BA现在已成为多效性信号代谢物，通过与生殖细胞编码受体的动态相互作用调节宿主代谢和炎症，肠道菌群我们已经证明Teff细胞上调外源性生物质转运蛋白的表达， MDR 1在回肠中限制氧化应激，防止病原性细胞因子分泌并抑制回肠炎。存在局部重吸收的BA。我们还鉴定了组成型雄烷受体（CAR）-BA- 免疫细胞中未知功能的敏感核受体-作为MDR 1（Abcb 1a）基因的驱动因子在粘膜Teff细胞中表达。Teff细胞中MDR 1或CAR的缺失或敲低导致严重的回肠炎。从机制上讲，我们的数据表明，CAR对通过激活多种药物加工酶的表达，在粘膜Teff细胞中的转运蛋白，包括MDR 1，以解毒BA和加强局部免疫稳态。这种机制与克罗恩病的理解和治疗直接相关，如：人Teff细胞中的表达在肠粘膜中显著增加;（ii）MDR 1功能丧失在肠粘膜中显著增加。在克罗恩病患者的一个子集中是明显的;和（iii）消胆胺，FDA批准的胆汁酸阻断BA重吸收进入回肠粘膜的螯合剂，在T细胞转移和克罗恩病的自发小鼠模型。此外，该机制建立了一个意想不到的新 BA的监管功能。我们提出的研究使用遗传学和药理学方法，以及克罗恩病的临床相关小鼠模型，以确定CAR及其转录靶标与BA相互作用以加强回肠中的免疫稳态。这些研究一起将揭示回肠局部免疫稳态的重要新途径，这对提高我们对人类克罗恩病的理解和治疗具有重要意义。