Biology of alveolar macrophages in aging and tuberculosis

该项目将确定衰老对肺泡巨噬细胞(AM)的影响以及它们与结核分枝杆菌的相互作用。 我们将讨论AM生物在老龄化过程中的变化如何影响老年人患空气传播的风险增加 感染，这是一个极未开发的领域。AM被归类为交替激活的巨噬细胞或更多 一般来说，免疫调节巨噬细胞能够清除气雾化颗粒，同时保持 最佳气体交换。这里的研究是基于一个新兴的概念，即随着年龄的增长，慢性低- 肺部发生分级炎症(炎症)，改变AM的表型和功能。我们的中央 假设衰老过程中的慢性肺部炎症与一种独特的炎症信号有关。 矛盾的是，这导致了对AM中结核分枝杆菌的早期控制，同时为随后的增强奠定了基础 生长和细菌传播。我们提出了一个新的假设，即这种情况是通过不受控制的方式发生的 激活特定的巨噬细胞免疫调节网络导致细胞迁移增强 肺、AM激活和病理。不同炎症过程的后果 年轻人与老年人的比较是，在年轻人中，免疫调节签名导致潜伏期的建立 含有较少结核分枝杆菌和免疫细胞的稳定肉芽肿。相比之下，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和 激活的免疫细胞驱动重新激活。我们已经开发了一个新的三阶段模型，将在3 具体目标：1)明确AM的年龄相关表型和免疫功能(阶段1)。表达特定的 将对成人/老年人和年轻人/老年人的受体、炎症调节剂和氧化剂进行比较 鼠标AMS。我们将定义调节细胞因子产生的初始信号通路，并确定是否 年龄增加了激活的AM在肺中的招募和滞留。2)确定AM摄取和控制 结核分枝杆菌在老年时，同时启动异常炎症信号网络(阶段2和3)。我们会比较一下 老年与青年肺泡巨噬细胞中结核分枝杆菌的吞噬、氧化反应、运输和细胞内生长。我们 还将表征老年AM中另一种由核因子-κβ1介导的信号通路，在 结核分枝杆菌感染，导致IL-10升高，并激活干扰素-α/β自分泌反馈环，维持IL-10 10和CCL2生产。3)明确AM异常炎症信号网络在 老年小鼠的感染过程，包括重新激活(阶段3)。我们将确定反常生物的活动 老龄小鼠体内感染过程中的信号网络。我们还将评估以下各项的重要性 使用阻滞剂促进老年小鼠结核分枝杆菌生长的特定信号网络组件。项目的全部内容 与其他项目和核心整合并向其提供信息。拟议的研究具有创新性，因为它们 提供对老龄化影响的第一次全面的、模型驱动的、比较的和机械的分析 老年人和小鼠AM功能的研究。

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.