Macrophage nuclear receptors, metabolism and immune effectors during health and M. tuberculosis infection

项目摘要/摘要 人类的肺，在调节肺泡内空气交换的同时，不断地暴露在污染物、过敏原和 微生物。常驻肺泡巨噬细胞(AM)必须在不损害肺泡的情况下清除污秽。因此，AMS 拥有一种独特的、高度调节的免疫反应，导致某些空气中某些物质的清除效率低下 微生物，特别是寄主适应的病原体，如结核分枝杆菌(M.tb)，它是 结核病是全球十大死因之一。AM的开发、维护和生物学方面都很差 了解，特别是对于人类巨噬细胞，以及关于当地环境的影响，例如 肺泡内的表面活性物质和局部产生的细胞因子，如转化生长因子β。未能完全 了解AM发育的分子事件和生物学造成的关键障碍 开发针对肺的新治疗策略。这项正在进行的研究的长期目标 程序是确定与转录调节和炎症相关的信号通路 决定AM生物学的代谢物以及这些代谢物如何被宿主适应的细胞内病原体所选择 M.TB，以促进其增长。实验室的新数据表明，结核分枝杆菌、表面活性蛋白和转化生长因子β 调节核受体(NRs)过氧化物酶体增殖物激活受体γ的表达 (PParγ)、REV-ERBα、NURR77和NURR1.NRs是一个结构保守、配体激活的大家族 转录因子，使巨噬细胞能够感知其局部环境并形成免疫 回应。在这一点上，NRs处于新陈代谢(特别是脂质和二十烷类化合物)的界面上，并且 免疫，并日益被认为与结核分枝杆菌的发病机制有关，但在上下文中尚未探讨 肺脏和结核分枝杆菌。了解NRS是否/如何合作以以下方式调节AM生物学至关重要 对结核分枝杆菌的冲击反应NRs的表达和功能受到严格的调控，以提供平衡的免疫 回应。这一建议的假设是，NRS改变二十烷类代谢和保护性免疫 反应，从而使AM更容易受到结核分枝杆菌的影响，并且结核分枝杆菌增加了内源选择 进一步抑制AM免疫反应以提高其存活率的途径。具体目标是：1) 测定表面活性物质和局部细胞因子对人巨噬细胞NR表达和活性的影响 2)新发现的PPARγ效应子的特征及其对脂质的调节 以及3)决定PPARγ、REV-ERBα、Nur77和Nurr1以及 PPARγ效应器是可行的宿主导向的结核病治疗靶点。人的AMS和易处理的模型 人血单核细胞来源的巨噬细胞(MDM)、生化和遗传技术以及小鼠 模型将被用来研究NRs及其效应器在结核病中的作用。由于NRS调节新陈代谢和 炎症在组织、基因和信号方面的特异性，这些发现打开了一扇全新的大门 在健康和结核分枝杆菌感染期间，一套可能对宿主在肺部的反应至关重要的生物学途径。

Project Summary/Abstract Human lungs, while mediating air exchange in the alveoli, are constantly exposed to pollutants, allergens, and microbes. Resident alveolar macrophages (AMs) must clear insults without damaging the alveoli. Thus, AMs possess a unique, highly regulated immune response that results in inefficient clearance of some airborne microbes, especially host-adapted pathogens like Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), a top 10 cause of death worldwide. AM development, maintenance and biology are poorly understood, especially for human macrophages and in regards to the effect of the local environment, e.g. surfactant, which lines the alveoli, and locally produced cytokines such as TGFβ. Failure to completely understand the molecular events underlying AM development and biology creates a critical barrier to developing new treatment strategies that target the lung. The long-term objective of this ongoing research program is to identify signaling pathways associated with transcriptional regulators and inflammatory metabolites that dictate AM biology and how these are co-opted by the host-adapted intracellular pathogen M.tb, to enhance its growth. New data in the laboratory indicate that M.tb, surfactant proteins and TGFβ regulate expression of the nuclear receptors (NRs) peroxisome proliferator-activated receptor gamma (PPARγ), Rev-erbα, Nur77, and Nurr1. NRs are a large family of structurally conserved, ligand activated transcription factors, which enable macrophages to sense their local environment and shape immune responses. In this regard, NRs sit at the interface of metabolism (particularly lipid and eicosanoid) and immunity, and are increasingly recognized as relevant to M.tb pathogenesis, yet are unexplored in the context of the lung and M.tb. It is critical to understand if/how NRs cooperate to regulate AM biology in ways that impact responses to M.tb. Expression and function of NRs are tightly regulated to provide a balanced immune response. The hypothesis for this proposal is that NRs modify eicosanoid metabolism and protective immune responses, thereby making AMs more susceptible to M.tb and that M.tb augments select endogenous pathways to further dampen the AM immune response to enhance its survival. The Specific Aims are to: 1) determine the effect of surfactant and local cytokines on human macrophage NR expression and activity and how this is modulated by M.tb, 2) characterize newly discovered PPARγ effectors and their regulation of lipid metabolism during M.tb infection, and 3) determine whether PPARγ, Rev-erbα, Nur77 and Nurr1, as well as PPARγ effectors, are viable host-directed therapeutic targets for TB. Human AMs and the tractable model of human blood monocyte-derived macrophages (MDMs), biochemical and genetic techniques, and mouse models will be used to study the role of NRs, and their effectors, in TB. Since NRs regulate metabolism and inflammation in a tissue, gene and signal-specific manner, these findings open the door to a completely new set of biological pathways likely to be critical to host responses in the lung, during health and M.tb infection.