Alveolar Macrophages as Age-Related Drivers of Disordered Tissue Repair

肺泡巨噬细胞作为紊乱组织修复的年龄相关驱动因素

• 批准号: 10417059
• 负责人: GR Scott Budinger
• 金额: $ 39.91万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417059
• 关键词: Aging; Air; Alveolar; Alveolar Macrophages; Alzheimer' s Disease; Animals; Area; Award; Caenorhabditis elegans; Cause of Death; Cells; Cessation of life; Chronic Kidney Failure; Clinical; Communicable Diseases; Complex; Data; Dementia; Disease; Effector Cell; Elderly; Electron Transport; Epithelial; Flow Cytometry; Friends; Functional disorder; Funding Opportunities; Genes; Genetic; Genetic Transcription; Healthcare; Hospitals; Immune; Immune System Diseases; Impaired cognition; Impairment; Infection; Influenza A virus; Inhalation; Injury; Instruction; Link; Lung; Mediating; Metformin; Mitochondria; Mitochondrial Electron Transport Complex I; Modernization; Morbidity - disease rate; Mus; Myocardial Infarction; Pathway interactions; Play; Pneumonia; Population; Predisposition; Proteomics; Recovery; Research; Risk; Role; Sentinel; Skeletal Muscle; Stress; Survivors; Testing; Tissues; Toxin; Transcriptional Activation; Translational Repression; Work; activating transcription factor; activating transcription factor 4; age related; aged; biological adaptation to stress; end of life; experimental study; healthspan; improved; influenza A pneumonia; inhibitor; injury and repair; juvenile animal; lung injury; lung repair; macrophage; man; monocyte; mortality; older patient; particle; pathogen; proteostasis; recruit; repair function; repaired; resilience; response; scavenger receptor; single-cell RNA sequencing; small molecule inhibitor; tissue repair; transcriptomics

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.

抽象的 年龄相关免疫功能障碍最重要的临床表现之一是免疫功能增强 肺炎是传染病最常见的死因，对肺炎的易感性和死亡率 全世界。出院后一年，老年肺炎幸存者患肺炎的风险增加 与年龄相关的疾病，包括持续性肺损伤、导致行动不便的骨骼肌功能障碍、 心肌梗塞、慢性肾病、痴呆和认知障碍。因此，肺炎是一种 限制生命终结时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，它们充当前哨细胞和效应细胞 对周围空气中吸入的颗粒、毒素和病原体做出反应。我们使用了因果组合 针对巨噬细胞的遗传实验以及流式排序的无偏转录组学和蛋白质组学分析 来自甲型流感感染小鼠肺部的细胞群表明，肺泡的修复功能 巨噬细胞在衰老过程中减少。这些发现与线粒体毒物兴奋作用的概念一致，即 源自 Morimoto 博士和 Chandel 博士的工作（项目 2）。他们发现低水平的抑制 线虫中的线粒体电子传递诱导了蛋白质稳态保护反应，从而增强了 衰老动物的恢复能力，而更剧烈的电子传输抑制是有毒的。在老鼠身上，我们发现 二甲双胍抑制肺泡巨噬细胞中复合物 I 的线粒体电子传递，从而诱导 响应环境压力的蛋白质稳态保护基因的表达。线粒体电子 运输通过整合的应激反应和转录激活与蛋白质稳态相关 因子 ATF4。一致地，我们发现了一种综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，即年龄 肺泡巨噬细胞修复功能的相关损伤可以通过短暂的低水平逆转 通过 ISR 和 ATF4 使用复合物 I 抑制剂抑制电子传递，同时阴燃激活 衰老过程中的这些途径会阻碍正常修复。我们将在三个相互关联的具体项目中检验这一假设 目标： 目的 1. 确定衰老的肺泡巨噬细胞中清道夫受体 Mertk 是否缺乏 损害甲型流感引起的损伤后的肺部修复。 目的2.确定二甲双胍是否可以通过恢复肺泡巨噬细胞的修复功能 抑制衰老过程中线粒体电子传递的复合物 I。 目标 3. 确定线粒体激活蛋白质稳态是否通过 eIF2？介导 翻译抑制和/或 ATF4 可改善衰老过程中损伤后的肺修复。