Activating proteostasis in aging resident macrophages to prevent muscle and cognitive dysfunction after pneumonia

激活老化常驻巨噬细胞中的蛋白质稳态，以预防肺炎后的肌肉和认知功能障碍

• 批准号: 10417061
• 负责人: Alexander Misharin
• 金额: $ 39.54万
• 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/10417061
• 关键词: Aging; Animals; Apoptotic; Award; Bacterial Pneumonia; Brain; Cell Proliferation; Chronic; Cognitive; Complex; Data; Dementia; Disease; Distant; Elderly; Endocrine; Exhibits; Flow Cytometry; Functional disorder; Funding Opportunities; Gene Expression; Genes; Genetic; Healthcare; Impaired cognition; Impairment; Individual; Infection; Influenza A virus; Instruction; Interleukin-6; Kidney; Learning; Link; Literature; Lung; Memory; Microglia; Mitochondria; Modernization; Molecular; Molecular Chaperones; Morbidity - disease rate; Motor; Mus; Muscle; Muscle function; Muscle satellite cell; Muscular Atrophy; Myocardial; Neurocognitive Deficit; Organ; Pathway interactions; Patients; Phagocytosis; Pharmacology; Phenocopy; Physiological; Pneumonia; Process; Proliferating; Recovery; Research; Risk; Signal Pathway; Signal Transduction; Skeletal Muscle; Survivors; Testing; Tissues; Up-Regulation; Viral Pneumonia; Viremia; activating transcription factor 4; age related; aged; behavior test; biological adaptation to stress; cognitive function; cognitive recovery; end of life; healthspan; improved; influenza A pneumonia; injury and repair; juvenile animal; lung injury; macrophage; mitochondrial metabolism; molecular marker; mouse model; prevent; proteostasis; receptor function; repaired; response; satellite cell; scavenger receptor; skeletal muscle wasting; targeted treatment; transcriptome; transcriptomics; ubiquitin-protein ligase

PROJECT SUMMARY Elderly pneumonia survivors are at increased risk of developing skeletal muscle atrophy that impairs mobility, dementia, and cognitive dysfunction, which are perhaps the most debilitating limitations to health-span in the elderly. We found critical features of this multiple organ dysfunction after pneumonia are recapitulated in mice, allowing us to use mouse models to elucidate mechanisms that can be targeted for therapy. In the first cycle of this award, we found that a systemic increase in IL-6 during influenza A-induced pneumonia was necessary for upregulation of the E3-ubiquitin ligase atrogin-1 and muscle wasting in both young and aged animals. While muscle function was rapidly restored in young animals, we never observed it to recover in older animals even months after pneumonia. We observed that muscle satellite cells necessary for muscle repair failed to proliferate after pneumonia in aged, but not in young animals, which was associated with decreased expression of the scavenger receptor Mertk. Genetic disruption of genes required for phagocytosis (Mertk, C3, Cx3cr1) in young animals phenocopied the impaired satellite cell proliferation after influenza A pneumonia in aged animals. In parallel studies in the brain, we found that while young mice recover cognitive function after influenza A infection, older animals develop persistent neurocognitive impairment. Highly sensitive transcriptomic profiling of flow sorted microglia showed aged microglia exhibited decreased expression of scavenger receptors, including Mertk. This was associated with reduced expression of genes related to axonogenesis, learning and memory in whole brain transcriptomes from aged compared with young animals after influenza A-induced pneumonia. Tissue resident muscle macrophages and microglia from young mice robustly activated the integrated stress response (ISR) after influenza A infection as evidenced by increased expression of Activating Transcription Factor-4 (Atf4) and molecular chaperones, but aged mice lacked this response. These preliminary data support our hypothesis that age-related loss of scavenger receptor function impairs phagocytosis in tissue resident macrophages necessary for the molecular and physiologic recovery of skeletal muscle and cognitive function after pneumonia. We will determine whether these age-related changes can be reversed by inhibition of mitochondrial complex I via the ISR and/or ATF4 in two interrelated specific aims: Aim1. To determine whether scavenger receptor activity in resident skeletal muscle macrophages and microglia and is necessary for the recovery of cognitive and skeletal muscle function after influenza A- induced pneumonia. Aim 2. To determine whether modulation of mitochondrial metabolism, the integrated stress response and/or ATF4 can restore scavenger function of the microglia and skeletal muscle macrophages to improve cognitive and motor function in aged mice after pneumonia.

项目概要 老年肺炎幸存者患骨骼肌萎缩的风险增加，从而损害活动能力， 痴呆症和认知功能障碍，这可能是人类健康寿命最严重的限制 老年。我们发现，肺炎后这种多器官功能障碍的关键特征在小鼠身上重现， 使我们能够使用小鼠模型来阐明可靶向治疗的机制。在第一个周期中 获得该奖项后，我们发现甲型流感诱发的肺炎期间 IL-6 的全身增加对于以下情况是必要的： E3-泛素连接酶 atrogin-1 的上调和年轻和老年动物的肌肉萎缩。尽管 年轻动物的肌肉功能迅速恢复，我们从未观察到老年动物的肌肉功能恢复，甚至 肺炎发生几个月后。我们观察到肌肉修复所需的肌肉卫星细胞未能增殖 老年动物肺炎后，但幼龄动物则不然，这与 清道夫受体 Mertk。年轻人吞噬作用所需基因（Mertk、C3、Cx3cr1）的遗传破坏 动物的表型复制了老年动物甲型流感肺炎后卫星细胞增殖受损的情况。在 在大脑中进行的平行研究中，我们发现虽然幼鼠在感染甲型流感后恢复了认知功能， 年老的动物会出现持续的神经认知障碍。高灵敏度的流转录组分析 分选的小胶质细胞显示，衰老的小胶质细胞表现出清道夫受体（包括 Mertk）表达减少。 这与轴突发生、学习和记忆相关基因的表达减少有关 甲型流感引起的肺炎后老年动物与年轻动物的脑转录组比较。组织 来自年轻小鼠的常驻肌肉巨噬细胞和小胶质细胞强烈激活了综合应激反应 (ISR) 甲型流感感染后，激活转录因子 4 (Atf4) 表达增加证明 和分子伴侣，但老年小鼠缺乏这种反应。 这些初步数据支持我们的假设，即与年龄相关的清道夫受体功能丧失会损害 组织驻留巨噬细胞的吞噬作用对于骨骼的分子和生理恢复是必需的 肺炎后的肌肉和认知功能。我们将确定这些与年龄相关的变化是否可以 通过 ISR 和/或 ATF4 抑制线粒体复合物 I 来逆转，达到两个相互关联的具体目标： 目标1。确定常驻骨骼肌巨噬细胞中的清道夫受体活性是否与 小胶质细胞，对于甲型流感后认知和骨骼肌功能的恢复是必需的 诱发肺炎。 目标 2. 确定线粒体代谢、综合应激反应是否受到调节 和/或ATF4可以恢复小胶质细胞和骨骼肌巨噬细胞的清道夫功能 改善肺炎后老年小鼠的认知和运动功能。