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.

医学研究的一个长期追求的目标是确定增加治疗有效性的方法。 免疫反应在这里，我们提出了一种通过增加细胞增殖来增加骨髓细胞功能的方法。 血管紧张素转换酶（ACE）的表达。我们证明：1）在自然条件下， 无论是人类还是小鼠，骨髓细胞在免疫应答中都会增加ACE的产生。 挑战.这是一种适应性反应，允许细胞更好地应对挑战。（二） 当这一过程被夸大，通过使用遗传手段，以增加ACE的表达， 巨噬细胞或中性粒细胞，结果是小鼠的能力显着增加， 针对各种免疫挑战的先天性和适应性免疫应答。的这种增加 这种反应直接归因于过表达的ACE蛋白的催化活性。3)增强的 免疫应答是ACE诱导的代谢变化的结果， 磷酸化和增加髓样细胞ATP。这与描述良好的髓样 LPS的代谢作用。ACE影响细胞ATP水平是一个非常新的发现， 在两个品系的小鼠中进行ATP水平的光谱测定和化学分析。相反，骨髓细胞 遗传缺乏ACE的人ATP减少，免疫功能下降。4)类似于基因ACE KO、ACE抑制剂（ACEi）可降低两种人的中性粒细胞超氧化物和抗菌反应 和老鼠。因此，髓系细胞表达ACE的水平， 骨髓细胞ATP含量和免疫反应的有效性。了解ACE如何影响 骨髓细胞免疫代谢将揭示一种全新的生物化学手段， 最终可能被操纵以增强人类反应的功能。在目标1中，我们检查 ACE表达增加的髓样细胞的详细代谢，以确定影响 免疫功能目的2：研究转录因子过氧化物酶体增殖物激活受体α（PPARα）在诱导细胞凋亡中的作用。 表达ACE增加的骨髓细胞的免疫表型。我们还想知道ACE活性如何诱导 细胞过氧化物酶体增殖物激活受体α增加。在目标3中，我们研究ACE是否作为一种自分泌或旁分泌因子， 我们是否可以表征负责影响细胞代谢的ACE肽产物， 增强骨髓细胞的免疫反应。