Role of SLCO3A1 in macrophage metabolite sensing and IBD

SLCO3A1 在巨噬细胞代谢物传感和 IBD 中的作用

• 批准号: 10581353
• 负责人: W. K. Eddie Ip
• 金额: $ 34.98万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-06 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581353
• 关键词: Anti-Inflammatory Agents; Bile Acids; Carrier Proteins; Cell membrane; Cells; Chronic; Colon; Data; Defect; Development; Exhibits; Genes; Goals; Health; Homeostasis; Immune response; Immunosuppression; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Knowledge; Large Intestine; Macrophage; Mediating; Metabolic Control; Metabolism; Molecular; Molecular Target; Organic Anion Transporters; Outcome; Pathogenesis; Pathway interactions; Phenotype; Prevention; Public Health; Research; Role; Shapes; Small Intestines; Tissues; Volatile Fatty Acids; cell growth regulation; cytokine; gut bacteria; gut dysbiosis; gut inflammation; gut microbiota; immunoregulation; innate immune function; innate immune sensing; insight; interest; microbial; novel; overexpression; receptor; uptake

PROJECT SUMMARY Intestinal health relies on the homeostatic function of intestinal macrophages in controlling gut inflammation. Defects in establishing this macrophage function can lead to unresolved inflammation as seen in inflammatory bowel disease (IBD). Recent studies have highlighted the impact of tissue microenvironments on establishing macrophage tissue-specific functions. Of specific interest, metabolites produced by gut bacteria, such as short-chain fatty acids and secondary bile acids, exert profound immunomodulatory effects on macrophage functional polarization. They suppress the expression of pro-inflammatory cytokines and transform macrophages to anti-inflammatory phenotype. What remains lacking, however, is the knowledge of how macrophages sense bacterial metabolites and mediate their immunomodulatory effects, especially in the gut microenvironment. Cellular metabolism regulates macrophage functions. We have previously demonstrated that macrophage pro-inflammatory response can be regulated by controlling metabolic substrate uptake. We therefore propose that metabolite sensing in macrophages is mediated via coordinated expression of transport proteins, which transport specific metabolites across plasma membranes and allow them to integrate into intracellular metabolism or to be directly sensed by intracellular receptors. Our long-term goal is to identify transporter targets that promote bacterial metabolite sensing and macrophage homeostatic function in order to control intestinal inflammation. Our preliminary data have indicated that macrophages exhibit distinct transporter reprogramming during functional polarization. There, we identified that SLCO3A1, an organic anion transporter and a recently discovered IBD-associated gene, is specifically upregulated during macrophage pro-inflammatory activation. Overexpression of SLCO3A1 enhances bile acid uptake. Also, the expression of SLCO3A1 is specific for tissue-resident macrophages from both small and large intestines as compared to other tissue-resident macrophages. Based on these observations, the overall goal of this project is to define the role of macrophage SLCO3A1 in metabolite sensing and intestinal tissue homeostasis. Our central hypothesis is that the expression of SLCO3A1 in macrophages facilitates the sensing of bacterial metabolites that promotes macrophage homeostatic function and the prevention of IBD. This project will focus on the following specific aims: (1) Define the mechanism by which SLCO3A1 regulates bile acid sensing and its immunosuppressive effect in macrophages. (2) Determine the role of SLCO3A1 in intestinal macrophages and the development of IBD. Altogether, this project will elucidate the mechanisms by which SLCO3A1 regulates the sensing of bacterial metabolites and promotes the homeostatic function of macrophages in controlling intestinal inflammation. We believe that completion of this project will provide mechanistic insights into important principles that govern the macrophage metabolite sensing in the intestinal microenvironment and the prevention of IBD.

项目摘要 肠道健康依赖于肠道巨噬细胞在控制肠道炎症中的稳态功能。 在建立这种巨噬细胞功能的缺陷可能导致未解决的炎症，如在 炎症性肠病（IBD）。最近的研究已经强调了组织微环境对 建立巨噬细胞组织特异性功能。特别令人感兴趣的是，肠道细菌产生的代谢物， 如短链脂肪酸和次级胆汁酸，对 巨噬细胞功能极化它们抑制促炎细胞因子的表达， 巨噬细胞的抗炎表型。然而，仍然缺乏的是如何做到这一点的知识。 巨噬细胞感知细菌代谢物并介导其免疫调节作用，特别是在肠道中 微环境细胞代谢调节巨噬细胞功能。我们之前已经证明， 巨噬细胞促炎反应可通过控制代谢底物摄取来调节。我们 因此，提出巨噬细胞中的代谢物传感是通过转运的协调表达介导的， 蛋白质，它运输特定的代谢物穿过质膜，并允许它们整合到 细胞内代谢或直接被细胞内受体感知。我们的长期目标是确定 促进细菌代谢物感知和巨噬细胞稳态功能的转运蛋白靶点， 控制肠道炎症。我们的初步数据表明，巨噬细胞表现出独特的转运蛋白， 在功能极化过程中进行重编程。在那里，我们确定了SLCO 3A1，一种有机阴离子转运蛋白， 和最近发现的IBD相关基因，在巨噬细胞促炎过程中特异性上调， activation. SLCO 3A1的过表达增强胆汁酸摄取。另外，SLCO 3A1的表达是特异性的 对于来自小肠和大肠的组织驻留巨噬细胞，与其他组织驻留巨噬细胞相比， 巨噬细胞基于这些观察，本项目的总体目标是确定巨噬细胞的作用 SLCO 3A1在代谢物传感和肠组织稳态中的作用我们的中心假设是， SLCO 3A1在巨噬细胞中的表达促进了细菌代谢物的感知， 体内平衡功能和IBD的预防。本项目将着重于以下具体目标：（1）界定 SLCO 3A1调节胆汁酸传感的机制及其在免疫抑制中的作用 巨噬细胞(2)确定SLCO 3A1在肠道巨噬细胞和IBD发展中的作用。 总之，本项目将阐明SLCO 3A1调节细菌对细菌的敏感性的机制。 代谢产物，并促进巨噬细胞在控制肠道炎症中的稳态功能。我们 我相信，这个项目的完成将提供对重要原则的机械见解， 巨噬细胞代谢物在肠道微环境中的感知和IBD的预防。