Mechanisms of GM-CSF-mediated metabolic regulation of monocyte function for control of pulmonary infection

GM-CSF介导的单核细胞功能代谢调节控制肺部感染的机制

• 批准号: 10462692
• 负责人: Xin Liu
• 金额: $ 9.46万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-05 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462692
• 关键词: ATP Citrate (pro-S)-Lyase; Acetates; Acetyl Coenzyme A; Address; Animal Model; Anti-Bacterial Agents; Antibiotic Therapy; Bacteria; Bacterial Infections; Bacterial Pneumonia; Cause of Death; Cell Differentiation process; Cell physiology; Cells; Communities; Complement; Data; Dendritic Cells; Development; Enzymes; Epigenetic Process; Exhibits; Fibrinogen; Glycolysis; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Histone Acetylation; Homeostasis; Host Defense; ITGAM gene; Immunocompromised Host; Immunologics; Immunotherapy; Infection; Infection Control; Inflammatory; Knockout Mice; Knowledge; Legionella pneumophila; Legionnaires' Disease; Lung infections; Maintenance; Mediating; Metabolic; Metabolic Control; Metabolism; Mitochondria; Mus; Myeloid Cells; Nosocomial pneumonia; Persons; Play; Pneumonia; Production; Pulmonary Inflammation; Regulation; Resolution; Respiration; Role; Signal Transduction; Source; Specificity; Testing; Tissues; aerobic glycolysis; base; blood glucose regulation; conditional knockout; cytokine; cytokine therapy; enhancing factor; glucose metabolism; histone acetyltransferase; in vivo; insight; lactate dehydrogenase A; loss of function; lung pathogen; monocyte; mortality; pneumonia treatment; reconstitution; response; restoration; targeted treatment

Pneumonia remains the leading infectious cause of death worldwide. Ly6Chi monocytes (iMCs) have an essential role in the maintenance of homeostasis and control of pulmonary infection. While it has now been recognized that the functions of iMCs are governed by microenvironment, the impact of local cytokine milieu on iMC function remains elusive. Granulocyte-macrophage colony-stimulating factor (GM-CSF), one of the most important host cytokines that modulate the functions of iMCs, plays a critical role in host defense against several significant pulmonary pathogens; however, the precise mechanisms by which GM-CSF regulates iMC function to control pulmonary infection is still not fully understood. My recent studies have discovered that GM-CSF promotes inflammatory cytokine production by iMCs and MC-derived cells for control of L. pneumophila infection, and that GM-CSF enhances aerobic glycolysis of MCs which is required for GM-CSF-dependent inflammatory cytokine production ex vivo. The goal of this proposal is to address the critical gap in knowledge regarding the mechanisms underlying GM-CSF-mediated metabolic regulation of iMC function for control of pulmonary infection in vivo. In my preliminary studies, I observed that inhibition of aerobic glycolysis in iMCs exhibited a significant reduction of inflammatory cytokine production during in vivo L. pneumophila infection, and that inhibition of histone acetyltransferase, a key enzyme downstream of Acetyl-CoA metabolism for histone acetylation, abolished GM-CSF-dependent inflammatory cytokine production ex vivo. These preliminary findings provoke the central hypothesis that GM-CSF supports iMC function for control of pulmonary infection through aerobic glycolysis-mediated epigenetic reprogramming. My central hypothesis will be tested by 3 aims: Aim 1 will test the hypothesis that GM-CSF supports iMC functional activities to control L. pneumophila infection. Aim 2 will test the hypothesis that GM-CSF regulates aerobic glycolysis of iMCs, which is required for MC-mediated antibacterial function. Aim 3 will test the hypothesis that aerobic glycolysis supports acetyl-CoA-mediated histone acetylation, which contributes to GM-CSF regulation of MC function. Overall, this proposal will provide insight into the mechanisms underlying GM-CSF-mediated metabolic control of iMC function against bacterial pneumonia.

肺炎仍然是全球主要的传染性死亡原因。Ly 6Chi单核细胞（iMC）具有重要的 在维持体内平衡和控制肺部感染中的作用。虽然现在已经认识到 iMC的功能受微环境控制，局部细胞因子环境对iMC功能的影响 仍然难以捉摸粒细胞-巨噬细胞集落刺激因子（GM-CSF）是最重要的宿主细胞之一 细胞因子调节iMC的功能，在宿主防御几种重要的免疫应答中起关键作用。 肺病原体;然而，GM-CSF调节iMC功能以控制 肺部感染仍然不完全清楚。我最近的研究发现GM-CSF能促进 通过iMC和MC衍生的细胞产生炎性细胞因子以控制L.嗜肺菌感染， GM-CSF促进MCs有氧糖酵解，这是GM-CSF依赖性炎症细胞因子所必需的 离体生产。本提案的目标是填补在以下方面的知识空白： GM-CSF介导的iMC功能代谢调节控制肺动脉高压的机制 体内感染。在我的初步研究中，我观察到抑制iMC中的有氧糖酵解表现出一种抑制作用， 在体内过程中显著减少炎性细胞因子产生L.嗜肺菌感染， 抑制组蛋白乙酰转移酶--组蛋白乙酰辅酶A代谢下游关键酶 乙酰化，消除了离体GM-CSF依赖性炎性细胞因子的产生。这些初步结果 提出了一个中心假设，即GM-CSF通过以下途径支持iMC控制肺部感染的功能： 有氧糖酵解介导的表观遗传重编程。我的中心假设将通过3个目标进行检验：目标1 将检验GM-CSF支持iMC控制L的功能活性的假设。嗜肺菌感染目的 2将检验GM-CSF调节iMC有氧糖酵解的假设，这是MC介导的糖酵解所必需的。 抗菌防霉作用目的3将检验有氧糖酵解支持乙酰辅酶A介导的组蛋白的假说 乙酰化，其有助于GM-CSF调节MC功能。总的来说，这一建议将提供洞察力， 研究GM-CSF介导的iMC抗细菌功能的代谢控制机制， 肺炎