ACE and myeloid cell metabolism

ACE 和骨髓细胞代谢

• 批准号: 10440789
• 负责人: KENNETH E BERNSTEIN
• 金额: $ 55.54万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-11 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440789
• 关键词: ACE2; Acute; Address; Affect; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Antibacterial Response; Biochemical; Blood Pressure; Cardiovascular system; Cell Respiration; Cell physiology; Cells; Cellular Metabolic Process; Chemicals; Chronic; Chronic Disease; Clinical; Data; Disease; Effectiveness; Enzymes; Genetic; Goals; Human; Immune; Immune response; Infection; Inflammatory; Knock-out; Learning; Link; Lipids; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Medical Research; Metabolic; Metabolism; Mus; Myelogenous; Myeloid Cells; Oxidative Phosphorylation; PPAR alpha; Paper; Peptides; Peptidyl-Dipeptidase A; Phenotype; Process; Production; Proteins; Ramipril; Role; Solid; Superoxides; adaptive immune response; autocrine; base; enzyme activity; enzyme mechanism; enzyme substrate; fighting; immune function; lipid metabolism; macrophage; neutrophil; novel; overexpression; paracrine; response; transcription factor; tumor; volunteer

A long sought goal of medical research is to identify ways to increase the effectiveness of the immune response. Here, we present a means of increasing myeloid cell function by increasing cell expression of angiotensin converting enzyme (ACE). We show that 1) under natural circumstances in both humans and mice, myeloid cells increase their production of ACE in response to immune challenge. This is an adaptive response that allows the cells to better respond to the challenge. 2) When this process is exaggerated by using genetic means to augment ACE expression in either macrophages or neutrophils, the result is a marked increase in the ability of mice to mount both an innate and adaptive immune response against a variety of immune challenges. This increase in response is directly due to the catalytic activity of the over-expressed ACE protein. 3) The enhanced immune response is the result of ACE-induced metabolic changes that increase oxidative phosphorylation and increase myeloid cell ATP. This is quite different from the well described myeloid metabolic effects of LPS. That ACE affects cell levels of ATP is a very new finding based on mass spectrometry and chemical analysis of ATP levels in two lines of mice. In contrast, myeloid cells genetically lacking ACE have reduced ATP and reduced immune function. 4) Similar to the genetic ACE KO, ACE inhibitors (ACEi) reduce neutrophil superoxide and anti-bacterial response in both humans and mice. Thus, there is a direct relationship between the level of ACE expression by myeloid cells, myeloid cell ATP content, and effectiveness of the immune response. Understanding how ACE affects myeloid cell immunometabolism will reveal a totally new biochemical means of enhancing myeloid function that might ultimately be manipulated to enhance human response. In Aim 1, we examine the detailed metabolism of myeloid cells with increased ACE expression to identify changes affecting immune function. In Aim 2, we will study the role of the transcription factor PPARα in inducing the immune phenotype of myeloid cells expressing increased ACE. We also ask how ACE activity induces increased cell PPARα. In Aim 3, we study whether ACE acts as an autocrine or paracrine factor and whether we can characterize the peptide product of ACE responsible for affecting cell metabolism and increasing the immune response of myeloid cells.

医学研究的长期扫描目标是确定提高效力的方法 免疫反应。在这里，我们提出一种通过增加细胞来增加髓样细胞功能的方法 血管紧张素转化酶（ACE）的表达。我们表明1）在自然情况下 人类和小鼠，髓样细胞都会因免疫而增加其ACE的产生 挑战。这是一种自适应反应，使细胞可以更好地应对挑战。 2） 当通过使用遗传手段增强ACE表达在任何一个中 巨噬细胞或中性粒细胞，其结果是小鼠安装两者的能力显着提高 对各种免疫挑战的先天和适应性免疫应答。这增加了 反应直接是由于ACE蛋白过表达的催化活性。 3）增强型 免疫反应是ACE诱导的代谢变化的结果，增加了氧化的氧化作用。 磷酸化并增加髓样细胞ATP。这与描述良好的髓样 LPS的代谢作用。 ACE影响ATP的细胞水平是基于质量的一个非常新的发现 两条小鼠的ATP水平的光谱和化学分析。相反，髓样细胞 从遗传上缺乏ACE已减少ATP和免疫功能降低。 4）类似于遗传王牌 KO，ACE抑制剂（ACEI）降低了两个人的中性粒细胞超氧化物和抗细菌反应 和老鼠。那就在髓样细胞的ACE表达水平之间存在直接关系， 髓样细胞ATP含量和免疫激素的有效性。了解王牌如何影响 髓样细胞免疫代谢将揭示一种全新的生化方法，以增强髓样 最终可以操纵以增强人类反应的功能。在AIM 1中，我们检查了 具有增加ACE表达的髓样细胞的详细代谢，以识别影响影响的变化 免疫功能。在AIM 2中，我们将研究转录因子PPARα在诱导的 表达的髓样细胞的免疫表型增加了ACE。我们还询问ACE活动如何引起 细胞PPARα增加。在AIM 3中，我们研究ACE是自身分泌还是旁分泌因子，并且 我们是否可以表征ACE的肽产物负责影响细胞代谢和 增加髓样细胞的免疫反应。