AhR ligands in epigenetic dysregulation of T cells

AhR 配体在 T 细胞表观遗传失调中的作用

• 批准号: 10075626
• 负责人: Mitzi Nagarkatti
• 金额: $ 3.08万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-10 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10075626
• 关键词: Acetylation; Algorithms; Anti-Inflammatory Agents; Autoimmune Diseases; Binding; Carbazoles; Cell Differentiation process; Cells; Chemicals; Clinical; Colitis; Complex; DNA Methylation; Data; Development; Diet; Dietary Indole; Dioxins; Disease; Disease model; Elements; Environment; Environmental Pollution; Epigenetic Process; Experimental Autoimmune Encephalomyelitis; Experimental Models; Expression Profiling; FOXP3 gene; Gene Expression; Genes; Health; IL17 gene; Immune response; Immunologics; Immunosuppression; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-17; Intervention; Knock-in Mouse; Lead; Lentivirus Vector; Ligands; Ligation; Mediating; Metabolism; Methylation; MicroRNAs; Modality; Modeling; Multiple Sclerosis; Nature; Outcome; Pathway interactions; Pharmacology; Phenotype; Play; Production; Promoter Regions; Property; Protein Family; Regulation; Regulatory T-Lymphocyte; Response Elements; Role; Site-Directed Mutagenesis; T cell differentiation; T-Lymphocyte; Testing; Tetrachlorodibenzodioxin; Toxic effect; Transfection; Tryptophan; Xenobiotic Metabolism; aryl hydrocarbon receptor ligand; base; epigenetic regulation; extracellular; histone methylation; histone modification; immune system function; immunoregulation; in silico; in vivo; inhibitor/antagonist; insight; knock-down; neuroinflammation; novel; novel therapeutics; overexpression; prevent; promoter; receptor; response; transcription factor

AhR is a cytosolic transcription factor that can be activated by wide range of chemicals including environmental contaminants, such as 2,3,7,8-Tetrachlorodibenzodioxin (TCDD), which leads to metabolism and regulation of toxic effects. AhR can also be activated by endogenous ligands and dietary compounds. Recent groundbreaking studies demonstrated that AhR activation can also regulate T cell differentiation, specifically the differentiation of Foxp3+ regulatory T cells (T regs) and proinflammatory Th17 cells that play a role in extracellular infections and autoimmune diseases such as multiple sclerosis (MS). Interestingly, AhR ligands were shown to have contrasting effects on Treg/Th17 differentiation, the reasons for which are not clear. For example, studies, including ours, demonstrated that some AhR ligands, such as TCDD, promoted the differentiation of Tregs while dampening that of Th17 cells, while a tryptophan photoproduct, 6-formylindolo[3,2-b]carbazole (FICZ), exerted contrasting effects. We have generated exciting preliminary data indicating that AhR activation triggers dysregulation in the microRNA (miR) expression and other epigenetic pathways. Based on the above, we will test the hypothesis that AhR-ligand complex may interact with dioxin response elements (DREs) on gene promoters of microRNAs as well as induce other epigenetic pathways, which together alter the expression of the miRs, which in turn, regulate the differentiation of encephalitogenic T cells. We will test our hypothesis using an experimental model of MS called Experimental Autoimmune Encephalomyelitis (EAE). In Aim1, we will test whether TCDD and FICZ induce unique miR expression profiles in purified Tregs/Th17 cells. Based on our preliminary data, we will focus on miR31-5p and miR1192 that target the expression of FoxP3 and IL-17. Specifically, we will examine whether the interactions of AhR-ligand complex with the DREs on these miR gene promoters are responsible for the disparate responses. In Aim 2, we will test whether the contrasting effect of TCDD and FICZ is due to differential DNA methylation/hydroxymethylation of these miR gene promoters as well as due to histone modifications. In Aim 3, we will determine whether miR mimics or antagomirs as well as pharmacological intervention of DNA methylation/hydroxymethylation and histone modification would reverse the inflammatory response and clinical outcome following ligation AhR with TCDD or FICZ. The proposed studies are highly significant in that we will identify novel epigenetic pathways triggered by AhR activation leading to immune regulation. Our studies will also provide novel information on whether targeting such epigenetic pathways in vivo can prevent and treat inflammatory and autoimmune diseases.

AHR是一种胞质转录因子，可被多种化学物质激活，包括 环境污染物，如2，3，7，8-四氯二苯二恶英(TCDD)，导致 毒性效应的代谢和调节。AHR也可被内源性配体激活 和膳食化合物。最近的突破性研究表明，AhR的激活可以 也调节T细胞分化，特别是Foxp3+调节性T细胞(T 和促炎性Th17细胞，在细胞外感染和自身免疫中发挥作用 多发性硬化症(MS)等疾病。有趣的是，AhR配体被证明具有 对Treg/Th17分化的影响不同，其原因尚不清楚。为 例如，包括我们在内的研究表明，一些AhR配体，如TCDD， 促进Tregs分化而抑制Th17细胞分化，而色氨酸 光产物6-甲酰并吲哚并[3，2-b]咔唑(FICZ)起到了反差的作用。我们有 产生了令人兴奋的初步数据，表明AhR激活触发了细胞内的失调 MicroRNA(MiR)的表达和其他表观遗传途径。在此基础上，我们将进行测试 AhR-配体复合体可能与二恶英反应元件相互作用的假说 (DRES)对microRNAs的基因启动子以及诱导其他表观遗传途径， 它们共同改变miRs的表达，进而调节分化 脑源性T细胞。我们将使用多发性硬化症的实验模型来检验我们的假设。 称为实验性自身免疫性脑脊髓炎(EAE)。在Aim1中，我们将测试TCDD是否 FICZ在纯化的Tregs/Th17细胞中诱导独特的miR表达谱。基于我们的 初步数据，我们将重点研究针对FoxP3表达的miR31-5p和miR1192 和IL-17。具体地说，我们将研究AhR-配体络合物与 这些miR基因启动子上的Dre是导致不同反应的原因。在目标2中，我们 将测试TCDD和FICZ的对比效应是否源于差异DNA 这些miR基因启动子的甲基化/羟甲基化以及组蛋白 修改。在目标3中，我们将确定miR是模仿还是对配子以及 DNA甲基化/羟甲基化和组蛋白修饰的药理学干预 会逆转AhR结扎后的炎症反应和临床结果 TCDD或FICZ。拟议的研究具有非常重要的意义，因为我们将发现 由AhR激活触发的表观遗传通路导致免疫调节。我们的研究将 还提供了新的信息，说明在体内靶向这种表观遗传途径是否可以 预防和治疗炎症性和自身免疫性疾病。