Nuclear Receptor Networks in Mucosal Immune Regulation

粘膜免疫调节中的核受体网络

• 批准号: 10459564
• 负责人: Matthew Eugene Pipkin
• 金额: $ 51.19万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-30 至 2022-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459564
• 关键词: Amplifiers; Anti-Inflammatory Agents; Antigens; Bacteria; Bile Acids; Bile fluid; Binding; Biochemical; Butyrates; CD4 Positive T Lymphocytes; Cell physiology; Cells; Colon; Data; Development; Duodenum; Effector Cell; Enteral; Enterocytes; Enterohepatic Circulation; Enzymes; Estrogens; FOXP3 gene; Foundations; Gallbladder; Gene Expression; Gene Expression Regulation; Genetic Screening; Genetic Transcription; Genome; Genomics; Glucocorticoid Receptor; Health; Hepatocyte; Histone Deacetylase; Homeostasis; Human; IL10 gene; Immune; Immune Tolerance; Immunologics; Immunology; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-10; Intestines; Large Intestine; Ligand Binding Domain; Ligands; Link; Liver; Location; Lymphocyte; Lymphocyte Subset; Maps; Metabolic; Metabolism; Microbe; Molecular; Mucosal Immunity; Mucositis; Mucous Membrane; Mus; Nuclear; Nuclear Hormone Receptors; Nuclear Receptors; Organ; Orphan; Peripheral; Production; RNA Interference; RNA interference screen; Receptor Activation; Regulation; Regulatory T-Lymphocyte; Reporting; Residual state; Role; Secondary to; Shapes; Small Intestines; T cell response; T-Lymphocyte; Testing; Thyroid Hormones; Time; Toxic effect; Ulcerative Colitis; Validation; Vitamin D3 Receptor; Volatile Fatty Acids; Wild Type Mouse; Xenobiotics; antagonist; constitutive androstane receptor; cytokine; design; functional genomics; host-microbe interactions; ileum; immunoregulation; in vivo; lipophilicity; member; microbial; microbiota; novel; novel strategies; programs; receptor; response; screening; sensor; small bowel Crohn' s disease; steroid hormone; targeted treatment; transcription factor

Project Summary The gut is a major immunological organ where host-microbe interactions shape both local and systemic immune tolerance. However, current views of intestinal immune regulation ignore fundamental differences in the function and metabolite composition of the two distinct organs that comprise the gut—the small and large intestine (or SI and LI). This impedes a more detailed understanding of immune regulatory mechanisms along the intestinal tract, and limits efforts to develop safer, more targeted treatments for the two major forms of human inflammatory bowel diseases (IBDs), ulcerative colitis and small bowel Crohn’s disease. We hypothesize that mucosal CD4 T cells use different sets of ligand-regulated nuclear receptors (NRs) in the SI and LI to control key regulatory functions, including IL-10 expression, to local concentration gradients of bile- and microbe-derived metabolites. On one hand, we have discovered that Foxp3– effector (Teff) subsets in the SI—including Th1 and Th17 cells— utilize the nuclear xenobiotic receptor, constitutive androstane receptor (CAR/Nr1i3), to direct a ‘hepatocyte-like’ transcriptional response to contend with high local bile acid (BA) concentrations, which are far greater in SI than in LI (millimolar vs micromolar) due to ‘enterohepatic’ circulation—where primary BAs synthesized in the liver, stored in the gallbladder, and secreted into the duodenum are actively reabsorbed by specialized enterocytes in the ileum for portal recirculation to the liver. Because BAs are lipophilic, they can be toxic and pro-inflammatory, and several nuclear receptors—including CAR—have evolved to suppress BA toxicity. These studies suggest that enterohepatic circulation establishes a unique SI microenvironment that is distinct from that in the LI and requires unique transcriptional machinery to protect T cells in the SI. Conversely, the LI harbors 103-107 times more bacteria than SI, and ~1000-fold lower BA concentrations. Accordingly, microbes and their metabolites— short chain fatty acids (SCFAs; e.g., butyrate), secondary BAs (produced via microbial metabolism of residual primary BAs)—are central to immune regulation in the LI. SCFAs inhibit histone deacetylase enzymes (HDACs) and stabilize Foxp3 gene expression in peripherally-induced T regulatory cells (iTregs), whereas secondary BAs appear to promote regulatory functions of RORgt+ Tregs in the LI through another NR, vitamin D receptor (VDR). Thus, while antigens from the enteric flora prime both pro- and anti-inflammatory T cell responses throughout the gut, marked concentration gradients of bile- and bacteria-derived metabolites in the SI vs. LI are sensed by different NRs to execute compartmentalized T cell regulatory functions. In testing this hypothesis, we will apply cutting-edge genomics and computational approaches to comprehensively map the contributions of each of the 49 mouse NRs to specialized regulatory functions in the SI and LI in vivo, using IL-10 expression as the primary screening target. We will also interrogate the regulation and molecular functions of two key NRs, CAR/Nr1i3 and VDR/Nr1i1, in SI type 1 regulatory (Tr1) and LI iTreg cells, respectively. These studies will advance understanding of lymphocyte specialization in the gut, and inform new approaches to treat IBDs.

项目摘要 肠道是宿主与微生物相互作用形成局部和系统免疫的主要免疫器官。 宽容。然而，目前关于肠道免疫调节的观点忽略了功能上的根本差异。 以及组成肠道的两个不同器官--小肠和大肠(或SI)的代谢物组成 和李)。这阻碍了对肠道免疫调节机制的更详细的了解。 肠道，并限制了开发更安全、更有针对性的治疗这两种主要形式的人类炎症的努力 肠道疾病(IBD)、溃疡性结肠炎和小肠克罗恩病。我们假设粘膜中的CD4T 细胞在SI和LI中使用不同的配体调节核受体(NRs)来控制关键的调节 功能，包括IL-10的表达，对胆汁和微生物来源的代谢物的局部浓度梯度。 一方面，我们发现在SI中，包括Th1和Th17细胞在内的Foxp3效应器(Tef)亚群。 利用核内异种受体--组成性雄烷受体(CAR/Nr1I3)，引导一种“肝细胞样” 转录反应与高的局部胆汁酸(BA)浓度相抗衡，后者在SI中远远高于SI 在Li(毫摩尔与微摩尔)中，由于‘肠-肝’循环--其中初级物质在肝脏中合成， 储存在胆囊中，并分泌到十二指肠，被特殊的肠细胞积极地重新吸收 回肠是门静脉再循环到肝脏的回肠。因为bas是亲脂性的，它们可能是有毒的和促炎的， 包括CAR在内的几种核受体已经进化出来抑制BA的毒性。这些研究表明 这种肠-肝循环建立了一种独特的SI微环境，这种微环境不同于LI和LI 需要独特的转录机制来保护SI中的T细胞。相反，李氏家族拥有103-107倍的财富 细菌数量比SI多，BA浓度低约1000倍。因此，微生物及其代谢物- 短链脂肪酸(SCFA；例如丁酸)、次级BAs(通过残留的微生物代谢产生) 初级bas)-是LI中免疫调节的中心。单链脂肪酸抑制组蛋白脱乙酰酶(HDAC) 并稳定外周诱导的T调节细胞(ITregs)中Foxp3基因的表达，而次级Bas 似乎通过另一种受体--维生素D受体(VDR)促进RORgt+Tregs在LI中的调节功能。 因此，虽然来自肠道菌群的抗原在整个过程中都启动了促炎和抗炎T细胞反应 在肠道中，SI和LI中胆汁和细菌衍生的代谢物的显著浓度梯度是通过 不同的NRs执行划分的T细胞调节功能。在检验这一假设时，我们将应用 尖端基因组学和计算方法，以全面绘制每一个 49小鼠NRs在体内对SI和LI具有专门的调节功能，以IL-10的表达为主要 筛选目标。我们还将询问两个关键NRs，Car/Nr1i3和Nr1i3的调节和分子功能 VDR/Nr1i1，分别在SI 1型调节细胞(TR1)和LI iTreg细胞中。这些研究将取得进展 了解肠道中淋巴细胞的特化，并提供治疗IBD的新方法。