Bile acid-dependent T cell regulation in the intestine

肠道内胆汁酸依赖性 T 细胞调节

• 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
• 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' 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

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、使人虚弱的特征。 炎症性肠病，克罗恩病。然而，调控局部免疫功能的机制 回肠的炎症仍不明确。这一建议提出了一种新的途径，通过这种途径 循环中的T细胞-包括产生干扰素的Th1细胞和分泌IL-17A的Th17细胞- 补偿回肠中胆汁酸(BAS)的细胞毒性浓度，以维护免疫平衡。 长期以来被认为是简单的乳化剂，它在肝脏和回肠之间循环，有助于 膳食脂肪的吸收和消除，BAs现在已经成为多效性信号代谢物， 通过与生殖系编码受体和受体的动态相互作用来调节宿主代谢和炎症 肠道微生物区系。我们已经证明，TJeff细胞上调了异种转运蛋白的表达， MDR1，限制氧化应激，防止致病细胞因子分泌，抑制回肠炎 存在局部再吸收的bas。我们还鉴定了构成雄烷受体(CAR)-a BA- 感知免疫细胞中未知功能的核受体--作为MDR1(Abcb1a)基因的驱动因素 在黏膜组织中的表达。TEF细胞中MDR1或CAR的丢失或敲除会导致严重的 在转移到免疫缺陷的RAG1-/-小鼠后发生回肠炎。从机制上讲，我们的数据表明汽车对 通过激活多种药物加工酶和蛋白的表达，促进回肠粘膜相关的bas 黏膜中的转运蛋白，包括mdr1，可以解毒bas并加强局部免疫平衡。 这一机制直接关系到对克罗恩病的认识和治疗，因为：(I)mdr1 人T细胞在肠粘膜中的表达显著增加；(Ii)mdr1功能丧失 在克罗恩病患者中很明显；和(Iii)胆碱胺，一种FDA批准的胆汁酸 阻滞剂阻止BA重新吸收到回肠粘膜，减轻T细胞转移和回肠炎症 自发性克罗恩病小鼠模型。此外，这一机制建立了一个意想不到的新 BAS的监管职能。我们建议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和其 转录靶标与bas相互作用，加强回肠的免疫平衡。总而言之，这些研究 将揭示回肠局部免疫动态平衡的重要新途径，同时具有 对提高我们对人类克罗恩病的认识和治疗有重要意义。