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

项目总结/摘要 人的肺在调节肺泡中的空气交换的同时，不断地暴露于污染物、过敏原和过敏原。 微生物常驻肺泡巨噬细胞（AM）必须清除损伤而不损害肺泡。因此，AM 具有独特的，高度调节的免疫反应，导致一些空气传播的 微生物，特别是宿主适应性病原体，如结核分枝杆菌（M.tb）， 结核病（TB）是全球十大死亡原因之一。AM发育、维持和生物学较差 理解，特别是对于人巨噬细胞和关于局部环境的影响，例如， 表面活性剂，其排列在肺泡上，以及局部产生的细胞因子如TGFβ。未能完全 了解AM发展和生物学背后的分子事件， 开发针对肺部的新治疗策略。这项研究的长期目标是 该项目旨在确定与转录调节因子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吸收 以促进其生长。实验室的新数据表明，结核分枝杆菌、表面活性蛋白和TGFβ 调节核受体（NR）过氧化物酶体增殖物激活受体γ的表达 (PPARγ）、Rev-erbα、Nur77和Nurr1。NR是结构保守的配体活化的大家族， 转录因子，使巨噬细胞能够感知其局部环境并形成免疫 应答在这方面，NR位于代谢的界面（特别是脂质和类二十烷酸）， 免疫，并越来越多地被认为是相关的结核分枝杆菌发病机制，但尚未探讨的背景下， 肺结核和肺结核了解NR是否/如何合作以调节AM生物学的方式至关重要， 对结核分枝杆菌的影响反应NR的表达和功能受到严格调节，以提供平衡的免疫 反应这一建议的假设是，NR修饰类花生酸代谢和保护性免疫。 反应，从而使AM更容易受到结核分枝杆菌和结核分枝杆菌增强选择内源性 途径，以进一步抑制AM免疫反应，以提高其生存。具体目标是：1） 确定表面活性剂和局部细胞因子对人巨噬细胞NR表达和活性的影响， 结核分枝杆菌如何调节这种作用，2）表征新发现的PPARγ效应物及其对脂质的调节 结核分枝杆菌感染过程中的代谢，以及3）确定是否PPARγ，Rev-erbα，Nur 77和Nurr 1，以及 PPARγ效应物是TB的可行的宿主导向治疗靶标。人类AM和易处理的 人血单核细胞衍生的巨噬细胞（MDM），生物化学和遗传技术，以及小鼠 模型将用于研究结核病中NRs及其效应物的作用。由于NR调节代谢， 炎症的组织，基因和信号特异性的方式，这些发现打开了大门，一个全新的 在健康和结核分枝杆菌感染期间，一组生物学途径可能对肺中的宿主反应至关重要。

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.