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: 10878367
• 负责人: Michael James Noto
• 金额: $ 47.98万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 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/10878367
• 关键词: Role; Mitochondrial; Metabolism; Neutrophilic; Lung

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.

总结 中性粒细胞在宿主防御病原体中的基本作用在动物中得到了很好的证实 感染模式和增加的易感性，感染性贫血患者。尽管如此，许多 嗜中性粒细胞生物学的各个方面仍有待研究。支持抗微生物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达到的可塑性程度知之甚少， 国家不知道。我们利用独特的方法来确定增加的 患者感染风险和Cpt1a多态性。肉毒碱棕榈酰转移酶1a（Cpt1a）是 长链脂肪酸的线粒体代谢。使用CPT 1a的药理学抑制剂和多种 在小鼠细菌性肺炎模型中，我们已经证明CPT1a抑制增加了对 通过减少中性粒细胞向感染部位的动员和感染部位的激活来抑制感染。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的模型的初步数据， 其对于放大嗜中性粒细胞活化、趋化性所需的活化信号是必需的， 抗菌功能基于这些发现，我们将检验脂肪酸代谢是 肺中中性粒细胞运输和抗菌防御的基本代谢程序。我们特别 将测试子假设，即（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，和（iii）脂肪酸代谢的破坏损害中性粒细胞的激活，趋化性， 抗菌防御和嗜酸性肺部炎症。具体目标1将定义脂肪酸的作用 代谢对中性粒细胞能量学、迁移和效应器功能的影响。这项工作将建立贡献 脂肪酸代谢对中性粒细胞线粒体ATP生成的影响，明确脂肪酸代谢的作用 在中性粒细胞活化中的作用，并确定脂肪酸代谢对中性粒细胞抗菌的重要性 功能协调发展的具体目标2将确定脂肪酸代谢失活对嗜酸性肺的影响 炎症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 感染肺微环境的异质性。此外，该目的将确定脂肪酸的影响， 代谢抑制作用。完成这些目标将建立脂肪酸 氧化作为一个重要的代谢程序，以支持抗菌中性粒细胞功能，并增加 目前流行的范式是中性粒细胞仅仅依赖有氧糖酵解作为代谢程序。此外，本发明的目的是， 这些研究将确定中性粒细胞异质性在感染部位的功能后果， 建立中性粒细胞可塑性作为疾病状态的潜在贡献者。最后，这些目标将提供一个 存在于人类中的Cpt1a多态性与 增加感染风险。