Role of SLCO3A1 in macrophage metabolite sensing and IBD

项目总结 肠道健康有赖于肠道巨噬细胞在控制肠道炎症方面的稳态功能。 建立这种巨噬细胞功能的缺陷可能会导致未解决的炎症，如 炎症性肠病。最近的研究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， 如短链脂肪酸和二次胆汁酸等，对人体有深刻的免疫调节作用 巨噬细胞功能极化。它们抑制促炎细胞因子的表达并将其转化为 巨噬细胞的抗炎表型。然而，仍然缺乏的是对如何 巨噬细胞感知细菌代谢物并调节其免疫调节作用，特别是在肠道 微环境。细胞代谢调节巨噬细胞的功能。我们之前已经证明过 巨噬细胞的促炎反应可以通过控制代谢底物摄取来调节。我们 因此提出巨噬细胞的代谢物感觉是通过转运的协调表达来调节的。 蛋白质，它通过质膜运输特定的代谢物，并允许它们整合到 细胞内代谢或被细胞内受体直接感觉到。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体靶标 控制肠道炎症。我们的初步数据表明，巨噬细胞表现出不同的转运体。 在功能极化期间重新编程。在那里，我们确定了SLCO3A1，一种有机阴离子转运体 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 激活。SLCO3A1的过表达增强了胆汁酸的摄取。此外，SLCO3A1的表达是特异的 与其他组织驻留的巨噬细胞相比，来自小肠和大肠的组织驻留的巨噬细胞 巨噬细胞。基于这些观察，这个项目的总体目标是确定巨噬细胞的作用 SLCO3A1在代谢物感知和肠道组织动态平衡中的作用。我们的中心假设是 巨噬细胞中SLCO3A1促进细菌代谢产物促进巨噬细胞的感觉 体内平衡功能与IBD的预防。该项目将侧重于以下具体目标：(1)确定 SLCO3A1调节胆汁酸感觉的机制及其免疫抑制作用 巨噬细胞。(2)探讨SLCO3A1在肠巨噬细胞中的作用及在IBD发病中的作用。 总之，本项目将阐明SLCO3A1调节细菌感官的机制 代谢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管理 肠道微环境中巨噬细胞代谢物的感知与IBD的预防。

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.