Mitochondrial metabolism and macrophage function post MI

心肌梗死后线粒体代谢和巨噬细胞功能

• 批准号: 10421059
• 负责人: Rong Tian
• 金额: $ 74.08万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10421059
• 关键词: Affect; Anabolism; Anti-Inflammatory Agents; Behavior; Biological Assay; Bone Marrow; Carbon; Cardiac; Cardiac health; Cells; ChIP-seq; Complex; Cues; Energy Metabolism; Epigenetic Process; Generations; Glycolysis; Heart; Heart Diseases; Immunology; Impairment; Infarction; Infiltration; Inflammatory Response; Interleukin-13; Interleukin-4; Lead; Leukocytosis; Ligands; Link; Lipopolysaccharides; Macrophage Activation; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Mouse Protein; Mus; Myelogenous; Myeloid Cells; Myocardial Infarction; NADH; NADP; Natural Immunity; Outcome; Oxidation-Reduction; Oxidative Phosphorylation; Oxygen Consumption; Pattern; Pentosephosphate Pathway; Phagocytosis; Phase; Phenotype; Play; Production; Proteins; RNA Sequences; Research; Respiration; Role; Signal Transduction; Site; System; Testing; Time; Toll-like receptors; Transcriptional Regulation; cytokine; heart function; histone methylation; histone modification; interest; ischemic injury; macrophage; metabolomics; mitochondrial metabolism; mortality; post intervention; recruit; therapeutic target; tissue repair; transcriptome; treatment effect; wound healing

Abstract Macrophages are key components of innate immunity system. It emerged recently that macrophages play critical roles in heart health and diseases. Following myocardial infarction (MI), macrophage is recruited in high number to the infarct site and acts as a key regulator in post-MI remodeling, generating proinflammatory signals early and reparative cues later. However, it is not well understood how macrophage function is regulated during the period of rapid change. Of interest, transcriptome analysis of macrophage in the infarct zone showed a time- dependent reprogramming of mitochondrial function during the first week post-MI when macrophage phenotype transitions from proinflammatory to reparative. This raises the question whether mitochondrial metabolism in macrophage is causally linked to the outcome of post-MI remodeling, and if so, what the underlying mechanisms are. Immunology research finds that macrophage activation is accompanied by global rewiring of the metabolic pathway. Proinflammatory macrophage, elicited by Toll-like receptor ligands lipopolysaccharide (LPS), shifts it energy metabolism from oxidative phosphorylation towards glycolysis. Such a metabolic switch is thought to favor rapid energy production and increased demand for biosynthesis, and fuel pentose phosphate pathway for NADPH generation, all lead to high levels of ROS and proinflammatory cytokines. On the other hand, the Th2 cytokines IL-4 and IL-13 induce alternative activation which promotes anti-inflammatory activity, wound healing and tissue repair, and presents the opposite metabolic pattern. Although the metabolic switch has been well described, questions remain whether differential metabolic activity (i.e., use of glycolysis versus mitochondrial respiration) is a coincidence, a consequence of changes in phenotype, or a direct driver of macrophage function. It is also unclear whether similar mechanisms apply to cardiac macrophages. To decipher the mechanistic role of mitochondrial function in macrophage phenotype, we analyzed the phenotype of macrophage with impaired mitochondrial respiration due to deletion of Ndufs4, a mitochondrial Complex I protein (KO). KO increased glycolysis and reduced oxygen consumption in bone marrow derived macrophage (BMDM), and demonstrated exacerbated inflammatory response to LPS stimulation. In mice with myeloid-specific deletion of Ndufs4 (mKO) we showed increased mortality and poor cardiac function after MI. These observations led us to hypothesize that mitochondrial function is a key regulator of macrophage polarization during post-MI remodeling and hence a potential therapeutic target. To test the hypothesis, we will investigate the mechanistic link between mitochondrial function and epigenetic reprogramming during stimulation in primary macrophages, and furthermore, test the effects of manipulating mitochondrial function in macrophage function and post-MI remodeling in mice.

摘要 巨噬细胞是天然免疫系统的关键组成部分。最近发现巨噬细胞在癌症的治疗中 在心脏健康和疾病中的作用心肌梗死（MI）后，巨噬细胞大量募集 并在心肌梗死后重塑中起关键调节作用， 和修复提示。然而，还没有很好地理解巨噬细胞的功能是如何调节的， 快速变化的时期。有趣的是，梗死区巨噬细胞的转录组分析显示， 心肌梗死后第一周，当巨噬细胞表型 从促炎性转变为修复性这就提出了一个问题， 巨噬细胞与心肌梗死后重塑的结果有因果关系，如果是这样，其潜在机制是什么 是.免疫学研究发现，巨噬细胞活化伴随着代谢系统的整体重新布线， 通路由Toll样受体配体脂多糖（LPS）诱导的促炎巨噬细胞将其转移到 从氧化磷酸化到糖酵解的能量代谢。这种代谢开关被认为 有利于快速的能源生产和生物合成的需求增加，和燃料戊糖磷酸途径， NADPH的产生，都导致高水平的ROS和促炎细胞因子。另一方面，Th 2 细胞因子IL-4和IL-13诱导交替激活，其促进抗炎活性、伤口愈合 和组织修复，并呈现相反的代谢模式。虽然新陈代谢的转换 所描述的，问题仍然存在是否差异代谢活性（即，使用糖酵解与线粒体 呼吸）是一种巧合，是表型变化的结果，或者是巨噬细胞功能的直接驱动因素。 目前还不清楚类似的机制是否适用于心脏巨噬细胞。为了破译机械作用 的线粒体功能在巨噬细胞表型，我们分析了巨噬细胞的表型与受损 线粒体呼吸由于Ndufs 4（一种线粒体复合物I蛋白（KO））的缺失。KO增加 糖酵解和减少骨髓源性巨噬细胞（BMDM）的耗氧量，并证明 加重了对LPS刺激的炎症反应。在骨髓特异性缺失Ndufs 4（mKO）的小鼠中 我们发现MI后死亡率增加，心脏功能差。这些观察使我们假设， 线粒体功能是心肌梗死后重塑过程中巨噬细胞极化的关键调节因子， 因此是潜在治疗靶点。为了检验这一假设，我们将研究 原代巨噬细胞刺激期间的线粒体功能和表观遗传重编程，以及 此外，测试操纵线粒体功能对巨噬细胞功能和MI后的影响。 在小鼠中重塑。