ACE and myeloid cell metabolism

医学研究的一个长期追求的目标是确定提高药物有效性的方法

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.