Immune effects of ACE over-expression in neutrophils

中性粒细胞中 ACE 过度表达的免疫效应

• 批准号: 10176383
• 负责人: KENNETH E BERNSTEIN
• 金额: $ 42.58万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-11 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176383
• 关键词: Affect; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Arthritis; Autoimmune; Bradykinin; Cardiovascular Physiology; Catalytic Domain; Cell Lineage; Cell physiology; Cells; Chemicals; Citric Acid Cycle; Data; Development; Diabetic Nephropathy; Disease; Enzymes; Exhibits; Experimental Autoimmune Encephalomyelitis; Giant Cells; Granuloma; Heart failure; Hematopoiesis; Human; Hypertension; Immune; Immune System Diseases; Immune response; Immunologics; Immunosuppression; In Vitro; Infection; Inflammatory; Kidney; Klebsiella pneumoniae; Knowledge; Laboratories; Leukocytes; MHC Class I Genes; Mass Spectrum Analysis; Measures; Metabolic; Modeling; Mus; Myeloid Cells; Myocarditis; NADPH Oxidase; Neutrophil Activation; Parasitic infection; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Peptidyl-Dipeptidase A; Pharmacologic Substance; Phenotype; Phosphorylation; Physiological; Physiology; Play; Production; Proteins; Pseudomonas aeruginosa; Regulation; Renin-Angiotensin System; Residual state; Resistance; Respiratory Burst; Role; Sepsis; Shapes; Snake Venoms; Superoxides; Urinary tract infection; Vasoconstrictor Agents; Vasodilator Agents; Work; blood pressure reduction; blood pressure regulation; enzyme activity; enzyme substrate; genetic manipulation; immune function; macrophage; male; methicillin resistant Staphylococcus aureus; monocyte; neutrophil; novel; overexpression; pathogen; peptide I; programs; receptor; reproductive; response; tumor

Abstract - Angiotensin converting enzyme (ACE) is a peptidase that plays an important role in blood pressure control. Millions of patients take ACE inhibitors. The first data suggesting that ACE affects immune function were old studies documenting enhanced ACE production by the monocytic lineage cells comprising a granuloma. When genetic manipulation in mice is used to force over-expression of ACE in neutrophils or in monocytes and macrophages, these cells respond with a marked enhancement of immune function, as measured in both tumor and infection models. For example, mice over expressing ACE in neutrophils (NeuACE mice) have increased resistance to MRSA, and better in vitro killing of MRSA, P. aeruginosa, and K. pneumoniae. ACE over-expression increased neutrophil production of superoxide by NADPH oxidase following MRSA challenge, an effect independent of the angiotensin II AT1 receptor. These are very surprising and novel discoveries. The immune enhancement, a functional supercharging, is what makes this work significant. Our hypothesis is that over-expression of ACE alters the production or destruction of a peptide that has a remarkable developmental and metabolic effect on myelomonocytic cells. The potential payoff of this work is that, previous to our studies, there was nothing to suggest that ACE would have these immune effects. In other words, there is a physiologic pathway that is still not well understood, the regulation of which can achieve a marked enhancement of myelomonocytic cell function. Should we be able to identify how ACE affects the immune response, we will have discovered something very novel that could be manipulated to augment the immune response. We propose to study 1) where in the developmental lineage of myelomonocytic cells, ACE over-expression begins to affect the phenotype of the developing cells; 2) what are the metabolic effects of ACE over-expression and which of the two ACE catalytic domains is responsible for the metabolic and enhanced immune response seen in these cells. These data will be incorporated into a systematic analysis using mass spectrometry to try to determine the ACE substrate responsible for the enhanced immune response; and 3) how ACE over-expression leads to enhanced neutrophil activation of NADPH oxidase and thus better killing of pathogens. Such knowledge will identify a powerful but heretofore unknown means of regulating and enhancing the immune response.

摘要-血管紧张素转换酶（ACE）是一种肽酶，在血管紧张素转化中起着重要作用。 血压控制。数百万患者服用ACE抑制剂。第一个数据表明， ACE影响免疫功能是旧的研究，记录了增强ACE的生产， 包括肉芽肿的单核细胞谱系细胞。当老鼠的基因操作被用来 迫使ACE在中性粒细胞或单核细胞和巨噬细胞中过度表达，这些细胞 免疫功能显著增强的反应，如在肿瘤和 感染模型。例如，在中性粒细胞中过表达ACE的小鼠（NeuACE小鼠）具有 对MRSA的抗性增加，并且对MRSA、铜绿假单胞菌和克雷伯菌的体外杀灭效果更好。 肺炎。ACE过表达增加中性粒细胞通过NADPH产生超氧化物 氧化酶的MRSA挑战后，一个独立的血管紧张素II AT 1受体的影响。 这些都是非常令人惊讶和新颖的发现。免疫增强，功能性 增压，是什么使这项工作意义重大。我们的假设是， ACE改变一种肽的产生或破坏，这种肽具有显著的发育和 对骨髓单核细胞的代谢作用。这项工作的潜在回报是， 在我们的研究中，没有任何证据表明ACE会有这些免疫效应。换句 换句话说，有一种生理途径仍然没有得到很好的理解，其调节 可以显著增强骨髓单核细胞的功能。我们是否应该 确定ACE如何影响免疫反应，我们将发现一些非常新颖的东西， 可以用来增强免疫反应我们建议研究1）在 在骨髓单核细胞的发育谱系中，ACE过表达开始影响 发育细胞的表型; 2）ACE过表达的代谢效应是什么 以及两个ACE催化结构域中的哪一个负责代谢和增强 这些细胞中的免疫反应。这些数据将被纳入一个系统的 使用质谱法分析，试图确定负责ACE底物， 增强的免疫应答;以及3）ACE过度表达如何导致增强的中性粒细胞 激活NADPH氧化酶，从而更好地杀死病原体。这些知识将识别 这是一种调节和增强免疫反应的强大但迄今未知的手段。