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 血压控制。数百万患者服用血管紧张素转换酶抑制剂。第一个数据表明 ACE 会影响免疫功能，旧研究记录了 ACE 的产生增强 包含肉芽肿的单核细胞谱系细胞。当对小鼠进行基因操作时 强制中性粒细胞或单核细胞和巨噬细胞中 ACE 过度表达，这些细胞 根据肿瘤和免疫功能的测量，免疫功能显着增强。 感染模型。例如，中性粒细胞过度表达 ACE 的小鼠（NeuACE 小鼠） 提高对 MRSA 的耐药性，并更好地体外杀灭 MRSA、铜绿假单胞菌和 K. 肺炎杆菌。 ACE 过度表达增加中性粒细胞通过 NADPH 产生超氧化物 MRSA 攻击后的氧化酶，其作用独立于血管紧张素 II AT1 受体。 这些都是非常令人惊讶和新颖的发现。增强免疫力，功能性 增压，是这项工作的重要意义所在。我们的假设是过度表达 ACE 改变肽的产生或破坏，该肽具有显着的发育和 对骨髓单核细胞的代谢作用。这项工作的潜在回报是，在 我们的研究表明，没有任何证据表明 ACE 会产生这些免疫作用。在其他方面 换句话说，有一个生理途径还没有被很好地理解，它的调节 可以实现骨髓单核细胞功能的显着增强。我们是否能够 确定 ACE 如何影响免疫反应，我们将会发现一些非常新奇的东西 可以操纵它来增强免疫反应。我们建议研究 1) 在哪里 骨髓单核细胞的发育谱系，ACE过度表达开始影响 发育细胞的表型； 2）ACE过度表达对代谢有何影响 两个 ACE 催化结构域中的哪一个负责代谢和增强 在这些细胞中观察到免疫反应。这些数据将被纳入系统 使用质谱分析来尝试确定负责该反应的 ACE 底物 增强免疫反应； 3) ACE 过度表达如何导致中性粒细胞增强 激活NADPH氧化酶，从而更好地杀死病原体。这些知识将识别 一种强大但迄今为止未知的调节和增强免疫反应的方法。