Biology of alveolar macrophages in aging and tuberculosis

该项目将确定老化对肺泡巨噬细胞（AM）的影响及其与结核分枝杆菌的相互作用。 我们将讨论如何改变AM生物学在老化过程中影响老年人的风险增加， 感染，这是一个尚未充分探索的领域。AM被分类为交替激活的巨噬细胞，或更多 通常，免疫调节巨噬细胞能够清除雾化颗粒，同时维持 最佳气体交换本文的研究是基于新出现的概念，即随着年龄的慢性低- 在肺中发生分级炎症（炎症），其改变AM表型和功能。我们的中央 一种假说认为，衰老过程中的慢性肺部炎症与一种独特的炎症信号有关， 这矛盾地导致AM中结核分枝杆菌的早期控制，同时为随后的增强 生长和细菌传播。我们提出了一个新的假设，即这是通过不受控制的 特定巨噬细胞免疫调节网络的激活导致细胞迁移增强， 肺、AM激活和病理学。不同的炎症反应顺序在 年轻人与老年人的区别在于，在年轻人中，免疫调节信号导致潜伏期的建立， 稳定的肉芽肿含有较少的结核分枝杆菌和免疫细胞。相反，在老年人中， 慢性炎症是潜伏期的建立，不稳定的肉芽肿含有更多的结核分枝杆菌， 激活的免疫细胞驱动再激活。我们开发了一个新的三阶段模型，将在3 具体目的：1）确定AM的年龄相关表型和免疫功能（第1阶段）。表达特定 受体、炎症调节剂和氧化剂将在成人/老年人和年轻人/老年人中进行比较 小鼠AM。我们将定义调节细胞因子产生的初始信号通路，并确定老年人是否 年龄增加肺中激活的AM的募集和保留。2)确定AM吸收和控制 老年结核分枝杆菌，同时启动异常炎症信号网络（阶段2和3）。我们将比较 老年与年轻AM中结核分枝杆菌的吞噬作用、氧化反应、运输和细胞内生长。我们 还将描述老年人AM中NF-κβ1介导的另一种信号通路， 结核分枝杆菌感染，导致IL-10增加，并激活IFN-α/β自分泌反馈环，维持IL-10的表达。 10和CCL 2生产。3)定义AM异常炎症信号网络在治疗过程中的影响。 老年小鼠的感染过程，包括再激活（第3阶段）。我们将确定异常的活动 老年小鼠体内感染过程中的信号网络。我们还将评估 特异性信号网络组分对使用阻断剂的老年小鼠中增强的结核分枝杆菌生长的影响。项目全面 与其他项目和核心整合并提供信息。拟议的研究是创新的，因为它们 提供第一个全面的，模型驱动的，比较和老龄化的影响机制分析 对老年人和小鼠AM功能的影响。

This project will determine the effect of aging on alveolar macrophages (AMs) and their interaction with M.tb. We will address how alterations in AM biology during aging impact the increased risk of the elderly to airborne infection, a greatly underexplored area. AMs are classified as alternatively activated macrophages or, more generally, immunoregulatory macrophages that enable clearance of aerosolized particulates while maintaining optimal gas exchange. The studies herein are based on the emerging concept that with aging chronic low- grade inflammation (inflammaging) occurs in the lung which alters AM phenotype and function. Our central hypothesis is that chronic lung inflammation during aging is associated with a unique inflammatory signature which paradoxically leads to early control of M.tb in AMs, while setting the stage for subsequent enhanced growth and bacterial dissemination. We put forth the novel hypothesis that this occurs through uncontrolled activation of a specific macrophage immunoregulatory network resulting in enhanced cellular immigration to the lungs, AM activation and pathology. The consequences of the different inflammatory sequences in the young vs. old is that in the young, the immunoregulatory signature results in establishment of latency with stable granulomas containing fewer M.tb and immune cells. In contrast, in the elderly the long-term effects of the chronic inflammation are establishment of latency with unstable granulomas containing more M.tb and activated immune cells that drive reactivation. We have developed a new three stage model to be explored in 3 specific aims: 1) Define age-related phenotype and immune function of AMs (Stage 1). Expression of specific receptors, inflammatory modulators and oxidants will be compared in adult/elderly human and young/old mouse AMs. We will define the initial signaling pathways that regulate cytokine production and determine if old age increases recruitment and retention of activated AMs in the lung. 2) Determine AM uptake and control of M.tb in old age while initiating an aberrant inflammatory signaling network (Stages 2 and 3). We will compare phagocytosis, oxidative responses, trafficking and intracellular growth of M.tb in AMs in old vs. young age. We will also characterize an alternative NF-κβ1-mediated signaling pathway in AMs from the elderly which, during M.tb infection, leads to increased IL-10, and activation of an IFN-α/β autocrine feedback loop that sustains IL- 10 and CCL2 production. 3) Define the impact of the AM aberrant inflammatory signaling network during the course of infection in old mice, including reactivation (Stage 3). We will determine activity of the aberrant signaling network during the course of in vivo infection of old mice. We will also assess the importance of specific signaling network components on enhanced M.tb growth in old mice using blockers. The project fully integrates with and informs the other projects and cores. The proposed studies are innovative in that they provide the first comprehensive, model-driven, comparative and mechanistic analyses of the effects of aging on human and mouse AM function in old age.