Immune effects of ACE over-expression in neutrophils

血管紧张素转换酶(ACE)是一种在血管紧张素转换酶中发挥重要作用的多肽酶。 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 血管紧张素转换酶对免疫功能的影响是旧的研究记录的增强血管紧张素转换酶产生 构成肉芽肿的单核细胞系细胞。当小鼠的基因操作被用来 血管紧张素转换酶在中性粒细胞或单核细胞和巨噬细胞中的过度表达 免疫功能显著增强，如在肿瘤和 感染模型。例如，中性粒细胞过度表达ACE的小鼠(NeuACE小鼠) 增加了对MRSA的耐药性，对MRSA、铜绿假单胞菌和K。 肺炎。血管紧张素转换酶过表达促进NADPH诱导的中性粒细胞产生超氧化物 耐甲氧西林金黄色葡萄球菌攻击后的氧化物酶，这种作用不依赖于血管紧张素II AT1受体。 这些都是非常令人惊讶和新颖的发现。免疫增强，一种功能性 超级增压，是这项工作意义重大的原因。我们的假设是过度表达 血管紧张素转换酶改变一种多肽的产生或破坏，这种多肽具有显著的发育和 对粒单核细胞的代谢影响。这项工作的潜在回报是，在此之前 我们的研究表明，没有任何证据表明ACE会有这些免疫作用。在其他 换句话说，有一条生理途径仍然没有被很好地理解，它的调节 能达到明显增强骨髓单核细胞的功能。我们是否应该能够 确定ACE是如何影响免疫反应的，我们将会发现一些非常新颖的东西 这可以被操纵来增强免疫反应。我们建议研究1)在哪里 骨髓单核细胞的发育谱系，ACE的过度表达开始影响 发育中细胞的表型；2)ACE过度表达对代谢的影响 而这两个ACE催化结构域中的哪一个负责代谢和增强 在这些细胞中看到的免疫反应。这些数据将被合并到一个系统的 用质谱仪分析试图确定负责的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，从而更好地杀灭病原体。这样的知识将会确定 一种强大但迄今未知的调节和增强免疫反应的方法。

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.