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: 10197742
• 负责人: GR Scott Budinger
• 金额: $ 40.11万
• 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/10197742
• 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/antagonist; 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 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 肺炎的敏感性和死亡率，这是传染病最常见的死亡原因 全世界。在出院后的一年，年长的肺炎幸存者的发展风险增加 与年龄相关的疾病，包括持续性肺损伤，骨骼肌功能障碍导致不动， 心肌梗塞，慢性肾脏疾病，痴呆和认知障碍。因此，肺炎是 在生命尽头限制健康范围的复杂发病率的网关。肺泡巨噬细胞是 肺泡空间中最丰富的居民免疫种群，在那里它们充当哨兵和效应细胞 这对环境空气中的吸入颗粒，毒素和病原体有反应。我们结合了因果关系 靶向巨噬细胞的基因实验，以及无偏的转录组和蛋白质组学分析。 流感A肺的细胞群体受感染小鼠的肺部群体表明肺泡的修复功能 在老化期间，巨噬细胞减少。这些发现与线粒体刺激的概念融合在一起 来自Morimoto博士和Chandel博士的作品（项目2）。他们发现低水平的抑制作用 秀丽隐杆线虫中的线粒体电子传输诱导了一种蛋白质的保护反应，从而增强了 衰老动物的弹性，而对电子传输的更明显抑制是有毒的。在老鼠中，我们发现 二甲双胍抑制肺泡巨噬细胞中复合物I处的线粒体电子转运，以诱导 响应环境应激的蛋白质抑制基因的表达。线粒体电子 传输通过综合应力响应和转录激活与蛋白质结合 因子ATF4。一致地，我们发现了一个综合应力反应的小分子抑制剂，Isrib， 流感A感染后，肺部修复加速。这些数据支持我们年龄的假设 肺泡巨噬细胞的修复功能的相关障碍可以通过短暂的低水平逆转 通过ISR和ATF4抑制具有复合I抑制剂的电子传输，同时激活 衰老期间的这些途径排除了正常的修复。我们将在三个相互关联的特定方面检验这一假设 目标： 目的1。确定是否缺乏老年肺泡巨噬细胞中的清道夫受体MERTK 流感A诱导的损伤后会损害肺修复。 目标2。确定二甲双胍是否可以通过 衰老过程中线粒体电子传输的复合物I的抑制。 目标3。确定是否通过EIF2？ 翻译抑制和/或ATF4可改善衰老期间受伤后的肺修复。