ACE and myeloid cell metabolism

ACE 和骨髓细胞代谢

• 批准号: 10570941
• 负责人: KENNETH E BERNSTEIN
• 金额: $ 56.64万
• 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/10570941
• 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; Enzyme Induction; Enzymes; Genetic; Goals; Human; Immune; Immune response; Infection; Inflammatory; Innate Immune Response; Knock-out; Learning; Link; Lipids; Macrophage; 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; enzyme activity; enzyme mechanism; enzyme substrate; fighting; immune function; lipid metabolism; 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寻找方法来增加治疗的有效性 免疫反应。在这里，我们提出了一种通过增加细胞来提高髓系细胞功能的方法。 血管紧张素转换酶(ACE)的表达。我们表明：1)在自然情况下， 人类和小鼠的髓系细胞都增加了ACE的产生，以应对免疫 挑战。这是一种适应性反应，使细胞能够更好地应对挑战。2) 当这一过程被夸大时，使用遗传手段来增强ACE的表达 巨噬细胞或中性粒细胞，其结果是小鼠的能力显著增加， 针对各种免疫挑战的先天性和获得性免疫反应。这一增长 反应直接归因于过度表达的ACE蛋白的催化活性。3)增强版 免疫反应是血管紧张素转换酶诱导的代谢变化增加氧化的结果 磷酸化，增加髓系细胞的ATP。这与描述得很好的髓系大不相同。 内毒素的代谢效应。血管紧张素转换酶影响细胞内三磷酸腺苷的水平是一项基于质量的非常新的发现 两系小鼠三磷酸腺苷水平的光谱分析和化学分析。相比之下，髓系细胞 遗传缺陷的血管紧张素转换酶降低了三磷酸腺苷和免疫功能。4)类似于遗传ACE 血管紧张素转换酶抑制剂(ACEI)降低中性粒细胞超氧化物和抗菌反应 还有老鼠。因此，髓系细胞表达ACE的水平与 髓系细胞的三磷酸腺苷含量和免疫反应的有效性。了解ACE如何影响 髓系细胞免疫代谢将揭示一种全新的增强髓系的生化手段 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表达增加的髓系细胞的详细代谢以确定影响 免疫功能。在目标2中，我们将研究转录因子pparα在诱导 表达血管紧张素转换酶升高的髓系细胞免疫表型。我们还询问ACE活动是如何导致 细胞PPARα增加。在目标3中，我们研究了血管紧张素转换酶是否作为自分泌或旁分泌因子，并 我们是否能确定ACE的多肽产物是否能影响细胞代谢和 增强髓系细胞的免疫反应。