TB and Innate Immune Regulation of Lung Macrophages

描述（由申请人提供）：肺位于环境和粘膜免疫系统之间的关键界面，吸入大量颗粒和微生物。如果这些药物转移到下气道，专门的肺泡先天免疫反应在清除它们的过程中起关键作用，同时保持肺泡薄膜的完整性。先天免疫细胞与微生物的初始相互作用对感染的最终结果至关重要，特别是对于在肺泡巨噬细胞（AMs）中存活的结核分枝杆菌（M.tb）。AMs上的模式识别受体能有效地检测微生物；然而，检测后的免疫反应受到高度调节，以抑制潜在的破坏性炎症。AMs产生平衡炎症反应（包括促炎性和抗炎性）的能力是可选活化巨噬细胞（aaMs）的特征，而AMs是其中的一个原型。虽然AMs可以有效地根除常规遇到的微生物，但由于微生物杀灭机制减少或减慢，它们通常无法对宿主适应的细胞内病原体这样做。因此，我们认为aam在结核分枝杆菌和其他空气传播感染因子的发病机制中起着重要作用，但它们在肺泡内的发育、维持和生物学机制尚不清楚，特别是对人类巨噬细胞和局部环境的影响，如表面活性剂成分。我们未能完全了解肺巨噬细胞发育和生物学背后的分子事件，这为我们开发针对肺的新治疗和疫苗策略创造了一个关键障碍。根据我们最近发表的工作和新的初步数据，结核分枝杆菌和肺泡表面活性剂成分上调促炎症的主要负调节因子，即PPAR？，并且该转录因子反过来调节几种先天免疫决定因子，我们假设1)肺微环境，特别是表面活性剂成分，通过增加PPAR？活性及其下游效应物；2)结核分枝杆菌与表面活性剂组分协同作用，增加PPAR？导致肺部对结核分枝杆菌的早期保护性免疫反应受到抑制的活性。我们的目标是：1)确定增加PPAR的生化途径？人巨噬细胞对表面活性剂和强毒结核分枝杆菌的表达及其免疫相关功能2)描述新型PPAR的作用？调控人巨噬细胞对结核分枝杆菌感染反应的效应物；3)确定PPAR的扰动是否？在巨噬细胞中改变毒力结核分枝杆菌的生长和一致的炎症和杀微生物反应。我们将利用人类am和单核细胞来源的巨噬细胞（MDMs），生化和遗传技术，以及一种新的小鼠模型来实现我们的目标。这个持续项目的广泛和长期目标是确定关键的信号通路和细胞内的“主调控因子”，这些调控因子在健康期间对表面活性剂的反应和在空气传播感染期间对结核分枝杆菌的反应中决定巨噬细胞的免疫生物学；并最终针对这些决定因素来增强肺部免疫力。

DESCRIPTION (provided by applicant): Lungs sit at a critical interface between the environment and the mucosal immune system where abundant particulates and microbes are inhaled. If these agents transit to the lower airways, specialized alveolar innate immune responses play a key role in their clearance while maintaining integrity of the thin alveolar membrane. The initial interaction of innate immune cells with microbes is critical to the ultimate outcome of infection, particularly for Mycobacterium tuberculosis (M.tb) which survives within alveolar macrophages (AMs). Pattern Recognition Receptors on AMs efficiently detect microbes; however, the immune responses following detection are highly regulated to enable dampening of potentially damaging inflammation. This ability of AMs to generate a balanced inflammatory response (both pro- and anti-) is characteristic of alternatively activated macrophages (aaMs) of which AMs are a prototype. While AMs effectively eradicate routinely encountered microbes, they often fail to do so for host-adapted intracellular pathogens due to reduced or slowed microbial killing mechanisms. Thus we believe that aaMs play an important role in the pathogenesis of M.tb and other air-borne infectious agents, yet their development, maintenance and biology within the alveoli remain poorly understood, especially for human macrophages and the effect of the local environment, e.g. surfactant components. Our failure to completely understand the molecular events underlying lung macrophage development and biology creates a critical barrier in our attempts to develop new treatment and vaccine strategies that target the lung. Based on our recently published work and new preliminary data that both M.tb and alveolar surfactant components up-regulate a major negative regulator of pro-inflammation, i.e. PPAR?, and that this transcription factor in turn regulates several innate immune determinants, we hypothesize that 1) the lung microenvironment, specifically surfactant components, directs the differentiation of AMs toward the aaM state by increasing PPAR? activity and its downstream effectors; and 2) M.tb acts in concert with surfactant components to increase PPAR? activity which results in a dampened early protective immune response to M.tb in the lung. Our aims are to: 1) determine the biochemical pathways that increase PPAR? expression and its immune-related functions in human macrophages in response to surfactant and virulent M.tb; 2) characterize the role of novel PPAR? effectors in the regulation of human macrophage responses to M.tb infection; and 3) determine whether perturbations in PPAR? in macrophages alter the growth of virulent M.tb and coincident inflammatory and microbicidal responses. We will use human AMs and monocyte-derived macrophages (MDMs), biochemical and genetic techniques, and a new mouse model to accomplish our goals. The broad, long-term objectives of this continuing program are to identify the key signaling pathways and intracellular "master regulators" that dictate macrophage immunobiology in response to surfactant during health and to M.tb during air-borne infection; and to ultimately target these determinants to boost lung immunity.