Alveolar Macrophages as Age-Related Drivers of Disordered Tissue Repair

摘要 与年龄相关的免疫功能障碍的最重要的临床表现之一是增强的 对肺炎的易感性和死亡率，肺炎是传染病死亡的最常见原因 国际吧在出院后的一年里，老年肺炎幸存者患上肺炎的风险增加。 与年龄相关的疾病，包括持续性肺损伤，导致不动的骨骼肌功能障碍， 心肌梗死、慢性肾病、痴呆和认知障碍。因此，肺炎是一种 在生命的尽头，限制健康寿命的复合发病率的门户。肺泡巨噬细胞是 肺泡腔中最丰富的常驻免疫群体，在那里它们充当哨兵和效应细胞 对吸入的颗粒、毒素和周围空气中的病原体作出反应。我们使用了因果关系的组合 靶向巨噬细胞的遗传实验以及流式细胞仪的无偏转录组学和蛋白质组学分析 细胞群，表明肺泡的修复功能， 巨噬细胞在衰老过程中减少。这些发现与线粒体兴奋效应的概念一致， Morimoto博士和Chandel博士的工作（项目2）。他们发现低水平的抑制 线粒体电子传递elegans诱导了蛋白质稳定保护反应， 衰老动物的恢复力，而更显着的抑制电子传递是有毒的。在老鼠身上，我们发现 二甲双胍抑制肺泡巨噬细胞复合物I的线粒体电子传递， 蛋白质稳态保护基因在环境胁迫下的表达。线粒体电子 转运通过整合的应激反应和转录的激活与蛋白质稳态相关 ATF 4因子。因此，我们发现了一种整合应激反应的小分子抑制剂ISRIB， 加速老年小鼠感染甲型流感后的肺修复。这些数据支持我们的假设，年龄- 肺泡巨噬细胞修复功能的相关损伤可通过短暂的低水平 通过ISR和ATF 4抑制复合物I抑制剂的电子传递，同时阴燃激活 这些通路在老化过程中排除了正常的修复。我们将在三个相互关联的具体案例中检验这一假设。 目的： 目标1.为了确定老年肺泡巨噬细胞中清道夫受体Mertk的缺乏是否 在甲型流感引起的损伤后损害肺修复。 目标2.确定二甲双胍是否可以通过以下途径恢复肺泡巨噬细胞的修复功能： 衰老过程中线粒体电子传递复合物I的抑制。 目标3.为了确定是否通过eIF 2？介导 翻译抑制和/或ATF 4改善老化期间损伤后的肺修复。

Abstract One of the most important clinical manifestations of age-related immune dysfunction is an enhanced susceptibility to and mortality from pneumonia, the most common cause of death from an infectious disease worldwide. In the year after hospital discharge older pneumonia survivors have an increased risk of developing age-related disorders including persistent lung injury, skeletal muscle dysfunction leading to immobility, myocardial infarction, chronic kidney disease, dementia and cognitive impairment. As such, pneumonia is a gateway for the compounding morbidity that limits healthspan at the end of life. Alveolar macrophages are the most abundant resident immune population in the alveolar space, where they serve as sentinel and effector cells that respond to inhaled particles, toxins and pathogens in the ambient air. We used a combination of causal genetic experiments targeting macrophages and unbiased transcriptomic and proteomic analyses of flow-sorted cell populations from the lungs of influenza A infected mice to suggest that the reparative function of alveolar macrophages is reduced during aging. These findings converge with the concept of mitochondrial hormesis that emerged from Dr. Morimoto and Dr. Chandel's work (Project 2). They found that low level inhibition of mitochondrial electron transport in C. elegans induced a proteostasis-protective response that enhanced the resilience of aging animals, while more dramatic inhibition of electron transport was toxic. In mice, we found that metformin inhibits mitochondrial electron transport at complex I in alveolar macrophages to induce the expression of proteostasis protective genes in response to environmental stress. Mitochondrial electron transport is linked with proteostasis through the integrated stress response and activation of the transcription factor ATF4. Consistently, we found a small molecule inhibitor of the integrated stress response, ISRIB, accelerated lung repair after influenza A infection in aged mice. These data support our hypothesis that age- related impairments in the reparative function of alveolar macrophages can be reversed by transient low level inhibition of electron transport with complex I inhibitors via the ISR and ATF4, while smoldering activation of these pathways during aging precludes normal repair. We will test this hypothesis in three interrelated Specific Aims: Aim 1. To determine whether deficiency of the scavenger receptor Mertk in aged alveolar macrophages impairs lung repair after influenza A-induced injury. Aim 2. To determine whether metformin can restore the reparative function of alveolar macrophages via inhibition of complex I of mitochondrial electron transport during aging. Aim 3. To determine whether mitochondrial activation of proteostasis through eIF2?-mediated translational inhibition and/or ATF4 improves lung repair after injury during aging.