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

基本信息

批准号：
10877377
负责人：
Xin Liu
金额：
$ 24.9万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-05 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10877377
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 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&apos 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 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

项目摘要

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.

肺炎仍然是全球死亡的主要感染原因。 Ly6chi单核细胞（IMC）具有必不可少的在维持体内平衡和控制肺部感染中的作用。虽然现在已经被认可 IMC的功能受微环境的控制，局部细胞因子环境对IMC功能的影响仍然难以捉摸。粒细胞 - 巨噬细胞菌落刺激因子（GM-CSF），最重要的宿主之一调节IMC功能的细胞因子在宿主防御中起着至关重要的作用肺病原体；但是，GM-CSF调节IMC功能的确切机制肺部感染仍未完全了解。我最近的研究发现GM-CSF促进 IMC和MC衍生细胞的炎性细胞因子可控制肺炎乳杆菌感染，并 GM-CSF增强了MC的有氧糖酵解，这是GM-CSF依赖性炎症细胞因子所需的生产离体。该提议的目的是解决有关知识的关键差距 GM-CSF介导的IMC功能的代谢调节的机制以控制肺体内感染。在我的初步研究中，我观察到IMC中有氧糖酵解的抑制作用表现出体内肺炎乳杆菌感染期间炎性细胞因子产生的大幅降低，并显着降低抑制组蛋白乙酰转移酶，这是乙酰-COA代谢下游的关键酶乙酰化，废除了GM-CSF依赖性炎症性细胞因子的生产。这些初步发现引发了中心假设，即GM-CSF支持IMC功能，以控制肺部感染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个目的测试：目标1 将测试GM-CSF支持IMC功能活性以控制肺炎乳杆菌感染的假设。目的 2将测试GM-CSF调节IMC的有氧糖酵解的假设，这是MC介导的抗菌功能。 AIM 3将检验以下假设：有氧糖酵解支持乙酰-COA介导的组蛋白乙酰化，有助于MC功能的GM-CSF调节。总体而言，该建议将提供见解进入GM-CSF介导的IMC功能的代谢控制的机制，针对细菌肺炎。