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

健康和结核分枝杆菌感染期间的巨噬细胞核受体、代谢和免疫效应器

• 批准号: 10457308
• 负责人: Larry S. Schlesinger
• 金额: $ 70.68万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-07 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457308
• 关键词: Agonist; Air; Allergens; Alveolar; Alveolar Macrophages; Alveolus; BCL2 gene; Biochemical Genetics; Biochemical Pathway; Biological; Biology; Cause of Death; Cell physiology; Clinical; Collectins; Data; Development; Drug Targeting; Eicosanoid Production; Eicosanoids; Environment; Event; Exposure to; Failure; Family; Family member; Gases; Gene Expression; Genes; Genetic Techniques; Genetic Transcription; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Health; Homeostasis; Human; Immune; Immune Response Genes; Immune response; Immune system; Immunity; Infection; Inflammation; Inflammatory; Inhalation; Interleukin-10; Laboratories; Ligands; Link; Lipids; Lung; Lung immune response; Lung infections; MCL1 gene; Maintenance; Mediating; Metabolic; Metabolism; Microbe; Modeling; Molecular; Mus; Mycobacterium tuberculosis; NR4A2 gene; Nuclear Receptors; PPAR alpha; PPAR gamma; PTGS2 gene; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Proteins; Pulmonary Surfactant-Associated Protein A; Pulmonary alveolar structure; Regulation; Research; Role; Route; S100A8 gene; Sales; Shapes; Signal Pathway; Signal Transduction; Tissues; Transforming Growth Factor beta; Tuberculosis; base; cellular development; cytokine; eicosanoid metabolism; global health; human model; immunoregulation; in vitro Model; in vivo; inhibitor; knock-down; lipid mediator; lipid metabolism; mRNA Expression; macrophage; monocyte; mouse model; nano-string; pathogen; pollutant; pre-clinical; programs; receptor expression; response; surfactant; therapeutic target; transcription factor; treatment strategy; tuberculosis treatment

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.

项目摘要/摘要 人肺在肺泡中介导空气交换时不断暴露于污染物，过敏原和 微生物。居民肺泡巨噬细胞（AMS）必须清除侮辱，而不会损坏肺泡。那，AMS 具有独特的，高度调节的免疫反应，导致某些空降的效率低下 微生物，尤其是宿主适应的病原体，例如结核分枝杆菌（M.TB），是一种病因 结核病（TB），全球死亡的十大原因。 AM开发，维护和生物学很差 理解齿，特别是对于人类巨噬细胞和当地环境的影响，例如 表面活性剂，将肺泡和局部产生的细胞因子（如TGFβ）进行。无法完全 了解AM开发和生物学基础的分子事件为 制定针对肺部的新治疗策略。这项正在进行的研究的长期目标 程序是确定与转录调节器和炎症相关的信号通路 决定AM生物学的代谢产物以及它们如何由宿主适应的细胞内病原体采用 M.TB，以增强其增长。实验室中的新数据表明M.TB，表面活性剂蛋白和TGFβ 调节核受体（NRS）过氧化物增生剂激活受体伽玛的表达 （PPARγ），Rev-ERBα，NUR77和Nurr1。 NR是一个大型结构保守的配体激活的家族 转录因子，这使巨噬细胞能够感知其本地环境并形成免疫 回答。在这方面，NRS位于代谢的界面（尤其是脂质和类花生素）和 免疫力，越来越被认为与M.TB发病机理有关，但在上下文中是出乎意料的 肺和M.TB。重要的是要了解/nrs是否以以下方式调节AM生物学 对M.TB的影响反应NR的表达和功能受到严格调节以提供平衡的免疫 回复。该提议的假设是NRS修改了类花生酸代谢并保护免疫 响应，从而使AMS更容易受到M.TB的影响，并且M.TB增加了内源性 进一步抑制AM免疫反应以增强其存活的途径。具体目的是：1） 确定表面活性剂和局部细胞因子对人巨噬细胞NR表达和活性以及 M.TB的调节如何调节，2）表征新发现的PPARγ效应及其调节脂质 M.TB感染期间的代谢，3）确定PPARγ，Rev-ERBα，Nur77和Nurr1以及 PPARγ效应是TB的可行宿主定向的治疗靶标。人类AMS和可拖动的模型 人血单核细胞衍生的巨噬细胞（MDMS），生化和遗传技术以及小鼠 模型将用于研究NRS及其效果在结核病中的作用。由于NRS调节新陈代谢和 这些发现以组织，基因和信号特异性方式的炎症打开了全新的门 在健康和M.TB感染期间，一组生物学途径对于在肺中宿主反应至关重要。