The Role of Mitochondrial Metabolism in Neutrophilic Lung Inflammation

线粒体代谢在中性粒细胞性肺部炎症中的作用

• 批准号: 10402391
• 负责人: Michael James Noto
• 金额: $ 47.98万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402391
• 关键词: Animal Model; Anti-Bacterial Agents; Autocrine Communication; Bacterial Pneumonia; Biology; Bone Marrow; Carnitine; Carnitine Palmitoyltransferase I; Cells; Chemotaxis; Clinical; Coupled; Data; Defect; Disease; Exhibits; Fatty Acids; Generations; Genes; Genetic Polymorphism; Health; Heterogeneity; Host Defense; Human; Immune; Impairment; Infection; Inflammation; Link; Lung; Mediating; Metabolic; Mitochondria; Modeling; Mus; Mutation; Natural Immunity; Neutrophil Activation; Oxidative Phosphorylation; Patients; Persons; Pharmacology; Phenotype; Population; Predisposition; Production; Pulmonary Inflammation; Regulation; Role; Signal Transduction; Site; Testing; Transferase; Work; aerobic glycolysis; antimicrobial; base; conditional knockout; fatty acid metabolism; fatty acid oxidation; fatty acid transport; infection risk; inhibitor; long chain fatty acid; migration; mitochondrial metabolism; mortality; mouse model; neutrophil; new therapeutic target; novel; pathogen; phenome; programs; recruit; response; trafficking; transcriptomics

SUMMARY The fundamental role of neutrophils in host defense against pathogens is well established from animal models of infection and the increased susceptibility to infection in neutropenic patients. Despite this, many aspects of neutrophil biology remain underexplored. The metabolic programs needed to support antimicrobial neutrophil functions are poorly understood and the degree of plasticity these cells may achieve in disease states is not known. We have leveraged unique approaches to identify a novel association between increased infection risk in patients and a polymorphism in Cpt1a. Carnitine palmitoyltransferase 1a (Cpt1a) is required for mitochondrial metabolism of long chain fatty acids. Using a pharmacologic inhibitor of CPT1a and multiple murine models of bacterial pneumonia, we have demonstrated that CPT1a inhibition increased susceptibility to infection by decreasing neutrophil mobilization to, and activation at, the site of infection. We provide additional preliminary data to support a model whereby neutrophil mitochondria metabolize fatty acids to generate ATP, which is necessary for amplification of activating signals required for neutrophil activation, chemotaxis, and antibacterial functions. Based on these findings, we will test the overall hypothesis that fatty acid metabolism is an essential metabolic program for neutrophil trafficking and antibacterial defense in the lung. Specifically, we will test the sub-hypotheses that (i) fatty acid metabolism is an important mechanism for mitochondrial ATP production in neutrophils, (ii) fatty acid-derived mitochondrial ATP is required for amplification of neutrophil activating signals, and (iii) disruption of fatty acid metabolism impairs neutrophil activation, chemotaxis, antibacterial defenses, and neutrophilic lung inflammation. Specific Aim 1 will define the role of fatty acid metabolism on neutrophil energetics, migration, and effector functions. This work will establish the contribution of fatty acid metabolism to mitochondrial ATP production in neutrophils, define the role of fatty acid metabolism in neutrophil activation, and determine the importance of fatty acid metabolism for neutrophil antibacterial functions. Specific Aim 2 will determine the effect of inactivation of fatty acid metabolism on neutrophilic lung inflammation. This work will use multiple single-cell approaches to define neutrophil plasticity and activation heterogeneity in the infected lung microenvironment. Further, this Aim will determine the effects of fatty acid metabolism inhibition on neutrophilic lung inflammation. Completion of these Aims will establish fatty acid oxidation as an essential metabolic program to support antimicrobial neutrophil functions and add to the current prevailing paradigm that neutrophils rely solely on aerobic glycolysis as a metabolic program. Further, these studies will determine the functional consequences of neutrophil heterogeneity at the site of infection and establish neutrophil plasticity as a potential contributor to disease states. Finally, these aims will provide a mechanistic framework for the clinical association between a Cpt1a polymorphism existing in the human population and increased infection risk.

概括 中性粒细胞在宿主防御病原体中的基本作用已从动物实验中得到充分证实 感染模型和中性粒细胞减少患者对感染的易感性增加。尽管如此，许多 中性粒细胞生物学的各个方面仍未得到充分探索。支持抗菌药物所需的代谢程序 对中性粒细胞的功能以及这些细胞在疾病中可能实现的可塑性程度知之甚少 状态未知。我们利用独特的方法来确定增加之间的新关联 患者的感染风险和 Cpt1a 的多态性。肉碱棕榈酰转移酶 1a (Cpt1a) 是必需的 长链脂肪酸的线粒体代谢。使用 CPT1a 药物抑制剂和多种 在细菌性肺炎的小鼠模型中，我们已经证明抑制 CPT1a 会增加对细菌性肺炎的易感性 通过减少中性粒细胞向感染部位的动员和激活来预防感染。我们提供额外的 支持中性粒细胞线粒体代谢脂肪酸产生 ATP 模型的初步数据， 这是放大中性粒细胞激活、趋化性和所需的激活信号所必需的 抗菌功能。基于这些发现，我们将检验脂肪酸代谢是 肺部中性粒细胞运输和抗菌防御的重要代谢程序。具体来说，我们 将检验子假设 (i) 脂肪酸代谢是线粒体 ATP 的重要机制 中性粒细胞的产生，(ii) 脂肪酸衍生的线粒体 ATP 是中性粒细胞扩增所必需的 激活信号，以及（iii）脂肪酸代谢的破坏损害中性粒细胞活化、趋化性， 抗菌防御和中性粒细胞性肺部炎症。具体目标 1 将定义脂肪酸的作用 代谢对中性粒细胞能量、迁移和效应功能的影响。这项工作将建立贡献 脂肪酸代谢对中性粒细胞线粒体 ATP 产生的影响，定义脂肪酸代谢的作用 中性粒细胞活化，并确定脂肪酸代谢对于中性粒细胞抗菌的重要性 功能。具体目标 2 将确定脂肪酸代谢失活对中性粒细胞肺的影响 炎。这项工作将使用多种单细胞方法来定义中性粒细胞的可塑性和激活 受感染肺部微环境的异质性。此外，该目标将确定脂肪酸的影响 对中性粒细胞性肺部炎症的代谢抑制。完成这些目标将建立脂肪酸 氧化作为支持抗菌中性粒细胞功能并增加 目前流行的范式认为中性粒细胞仅依赖有氧糖酵解作为代谢程序。更远， 这些研究将确定感染部位中性粒细胞异质性的功能后果 确定中性粒细胞可塑性是疾病状态的潜在因素。最后，这些目标将提供 人类中存在的 Cpt1a 多态性之间临床关联的机制框架 人口和感染风险增加。