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：
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
项目类别：
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&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 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

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.

肺炎仍然是全球主要的传染性死亡原因。 Ly6Chi 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发挥作用。虽然现在已经被认可了 iMCs的功能受微环境调控，局部细胞因子环境对iMCs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），最重要的宿主之一调节 iMC 功能的细胞因子在宿主防御多种重要疾病中发挥着关键作用肺部病原体；然而，GM-CSF 调节 iMC 功能以控制的精确机制肺部感染尚不完全清楚。我最近的研究发现 GM-CSF 促进 iMC 和 MC 衍生细胞产生炎症细胞因子以控制嗜肺军团菌感染，并且 GM-CSF 增强 MC 的有氧糖酵解，这是 GM-CSF 依赖性炎症细胞因子所必需的离体生产。该提案的目标是解决有关以下方面的知识的关键差距： GM-CSF介导的iMC功能代谢调节控制肺功能的机制体内感染。在我的初步研究中，我观察到 iMC 中有氧糖酵解的抑制表现出体内嗜肺军团菌感染期间炎症细胞因子的产生显着减少，并且抑制组蛋白乙酰转移酶，组蛋白乙酰辅酶 A 代谢下游的关键酶乙酰化，消除了离体 GM-CSF 依赖性炎症细胞因子的产生。这些初步发现提出了一个中心假设：GM-CSF 通过支持 iMC 功能来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 个目标进行检验：目标 1 将检验 GM-CSF 支持 iMC 功能活动以控制嗜肺军团菌感染的假设。目的 2 将检验 GM-CSF 调节 iMC 有氧糖酵解的假设，这是 MC 介导的必需的抗菌功能。目标 3 将检验有氧糖酵解支持乙酰辅酶 A 介导的组蛋白的假设乙酰化，有助于 GM-CSF 对 MC 功能的调节。总体而言，该提案将提供见解 GM-CSF 介导的 iMC 功能代谢控制对抗细菌的潜在机制肺炎。