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.

项目摘要 肠道是主要的免疫器官，宿主 - 微生物相互作用塑造了局部和全身免疫 宽容。但是，目前对肠道免疫调节的看法忽略了功能的基本差异 以及构成肠道的两个不同的器官的代谢物组成 - 小肠和大肠（或Si） 和li）。这阻碍了对沿肠道免疫调节机制的更详细的理解 区域，并限制为两种主要形式的人类炎症形式开发更安全，更有针对性的治疗方法 肠病（IBD），溃疡性结肠炎和小肠克罗恩病。我们假设粘膜CD4 T 细胞使用SI和LI中的不同配体调节的核接收器（NRS）来控制关键调节 胆汁和微生物衍生代谢物的局部浓度梯度在内的功能，包括IL-10表达。 一方面，我们发现SI中的Foxp3效应子（TEFF）子集，包括Th1和Th17细胞 - 利用核异种生物受体，构成雄烷受体（CAR/NR1I3），指导“肝细胞样” 转录反应对高局部胆汁酸（BA）浓度的竞争，在SI中远大于 在李（毫米与微摩尔）中，由于“肠ep骨”圆而引起 存放在胆囊中，并被分泌到十二指肠中，被专门的肠细胞重新吸收 向肝脏再循环的回肠。因为BAS是亲脂性的，所以它们可能是有毒的和促炎的，所以 以及包括汽车在内的几个核接收器已进化为抑制BA毒性。这些研究表明 该肠球皮圆圈建立了独特的Si微环境，与Li和 需要独特的转录机械来保护SI中的T细胞。相反，Li Harbors 103-107次 细菌比SI多，BA浓度低约1000倍。彼此之间，微生物及其代谢物 - 短链脂肪酸（SCFA； 初级BAS） - LI中的免疫调节至关重要。 SCFA抑制组蛋白脱乙酰基酶（HDACS） 并稳定外周诱导的T调节细胞（ITREGS）中的FOXP3基因表达，而次级BAS 通过另一种NR维生素D受体（VDR），似乎可以促进LI中RORGT+ Treg的调节功能。 那虽然来自肠植物植物素的抗原均具有促和抗炎的T细胞反应 Si vs. Li中胆汁和细菌代谢物的肠道，标记的浓度梯度。 不同的NRS执行分隔的T细胞调节函数。在检验该假设时，我们将适用 尖端的基因组学和计算方法，用于全面绘制每个的贡献 49小鼠NRS在Si和Li In Vivo中的专门调节功能，使用IL-10表达作为主要的表达 筛选目标。我们还将询问两个关键NR的调节和分子函数，CAR/NR1I3和 VDR/NR1I1，在SI 1型调节（TR1）和LI ITREG细胞中。这些研究将进步 了解肠道中的淋巴细胞专业化，并为治疗IBD的新方法提供信息。