ACE and myeloid cell metabolism

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.

Grant Number: 5R01AI164519-05
NIH Institute/Center: NIH
Principal Investigator: KENNETH BERNSTEIN