Nuclear Receptor Networks in Mucosal Immune Regulation

粘膜免疫调节中的核受体网络

• 批准号: 10591752
• 负责人: Matthew Eugene Pipkin
• 金额: --
• 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 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591752
• 关键词: Nuclear; Receptor; Networks; Mucosal; Immune

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.

项目概要 肠道是一个主要的免疫器官，宿主与微生物的相互作用塑造局部和全身免疫 然而，目前肠道免疫调节的观点忽视了功能的根本差异。 以及构成肠道的两个不同器官——小肠和大肠（或 SI 和 LI）这阻碍了对肠道免疫调节机制的更详细的了解。 道，并限制了为人类两种主要炎症形式开发更安全、更有针对性的治疗方法的努力 肠道疾病 (IBD)、溃疡性结肠炎和小肠克罗恩病 我们​​勇敢地面对粘膜 CD4 T。 细胞使用 SI 和 LI 中不同组的配体调节核受体 (NR) 来控制关键调节 功能，包括 IL-10 表达，与胆汁和微生物衍生代谢物的局部浓度梯度相关。 一方面，我们发现 SI 中的 Foxp3 效应子 (Teff) 亚群（包括 Th1 和 Th17 细胞） 利用核异生素受体、组成型雄甾烷受体 (CAR/Nr1i3) 来指导“肝细胞样” 应对高局部胆汁酸 (BA) 浓度的转录反应，SI 中的胆汁酸浓度远高于 由于“肠肝”循环，初级 BA 在肝脏中合成，导致 LI（毫摩尔与微摩尔） 储存在胆囊中并分泌到十二指肠中，并被专门的肠细胞主动重吸收 由于 BA 是亲脂性的，因此它们可能具有毒性和促炎性， 这些研究表明，包括 CAR 在内的几种核受体已经进化出抑制 BA 毒性的能力。 肠肝循环建立了一个独特的 SI 微环境，与 LI 中的微环境不同， 需要独特的转录机制来保护 SI 中的 T 细胞离线，LI 包含 103-107 倍。 比 SI 更多的细菌，并且 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）、次生 BA（通过残余物的微生物代谢产生） 初级 BA）——SCFA 抑制组蛋白脱乙酰酶 (HDAC) 的免疫调节核心。 和 Foxp3 基因在外周诱导的 T 调节细胞 (iTreg) 中表达，而次级 BA 似乎通过另一种 NR、维生素 D 受体 (VDR) 促进 LI 中 RORgt+ Tregs 的调节功能。 因此，虽然来自肠道菌群的抗原在整个过程中引发促炎和抗炎 T 细胞反应 在肠道中，SI 与 LI 中胆汁和细菌衍生代谢物的显着浓度梯度由 在检验这一假设时，我们将应用不同的 NR 来执行区室化的 T 细胞调节功能。 尖端的基因组学和计算方法来全面绘制每个基因组的贡献 49 小鼠体内 SI 和 LI 中专门调节功能的 NR，使用 IL-10 表达作为主要 我们还将探讨两个关键 NR CAR/Nr1i3 和 CAR/Nr1i3 的调控和分子功能。 VDR/Nr1i1，分别在 SI 1 型调节 (Tr1) 和 LI iTreg 细胞中 这些研究将取得进展。 了解肠道淋巴细胞的专门化，并为治疗 IBD 提供新方法。