Mitochondrial metabolism and macrophage function post MI

摘要 巨噬细胞是天然免疫系统的重要组成部分。最近发现，巨噬细胞发挥着关键作用。 在心脏健康和疾病中的作用。心肌梗死后巨噬细胞大量聚集 并在心肌梗死后重塑中起关键调节作用，早期产生促炎信号 以及稍后的修复线索。然而，目前尚不清楚巨噬细胞的功能是如何在 快速变化的时期。有趣的是，对梗死区巨噬细胞的转录组分析显示， 心肌梗死后第一周巨噬细胞表型时线粒体功能的依赖性重编程 从促炎到修复的转变。这就提出了一个问题，即线粒体新陈代谢是否 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，潜在的机制是什么？ 是。免疫学研究发现，巨噬细胞的激活伴随着代谢的整体重新连接 路径。由Toll样受体配体脂多糖(LPS)诱导的促炎巨噬细胞使其 能量代谢从氧化磷酸化到糖酵解。这种新陈代谢的转变被认为 有利于快速的能源生产和增加对生物合成的需求，并为磷酸戊糖途径提供燃料 NADPH的产生，都会导致高水平的ROS和促炎细胞因子。另一方面，Th2 细胞因子IL-4和IL-13诱导交替激活，促进抗炎活性，伤口愈合 和组织修复，并呈现相反的新陈代谢模式。尽管新陈代谢的变化一直很好 如上所述，问题仍然是差异代谢活动(即糖酵解与线粒体的使用 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。 目前也不清楚类似的机制是否适用于心脏巨噬细胞。破译机械论的作用 关于线粒体功能的巨噬细胞表型，我们分析了受损的巨噬细胞的表型 线粒体呼吸是由于线粒体复合体I蛋白(KO)Ndufs4缺失所致。KO增加 骨髓源性巨噬细胞(BMDM)的糖酵解和减少氧耗，并证明 加重对内毒素刺激的炎症反应。髓系特异性缺失Ndufs4(MKO)的小鼠 我们发现心肌梗死后死亡率增加，心功能不佳。这些观察结果使我们假设 线粒体功能是心肌梗死后重构过程中巨噬细胞极化的关键调节因素 因此，它是一个潜在的治疗靶点。为了检验这一假设，我们将调查两者之间的机械联系 原代巨噬细胞刺激过程中的线粒体功能和表观遗传重编程 此外，测试操纵线粒体功能对巨噬细胞功能和心肌梗死后的影响 小鼠的重塑。

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.