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Angiotensin converting enzyme enhances the oxidative response and bactericidal activity of neutrophils

Zakir Khan, Xiao Z. Shen, Ellen A. Bernstein, Jorge F. Giani, Masahiro Eriguchi, Tuantuan V. Zhao, Romer A. Gonzalez-Villalobos, Sebastien Fuchs, George Y. Liu and Kenneth E. Bernstein

Key points

  • ACE plays an important physiological role in neutrophil anti-bacterial activity.

  • In mice, up-regulation of ACE in neutrophils strongly enhances bactericidal activity via increased NADPH oxidase production of ROS.

Abstract

Angiotensin converting enzyme (ACE) inhibitors are widely used to reduce blood pressure. Here, we examined if ACE is important for the antibacterial effectiveness of neutrophils. ACE knockout mice or mice treated with an ACE inhibitor were more susceptible to bacterial infection by methicillin-resistant S. aureus (MRSA). In contrast, 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 overexpression increased neutrophil production of reactive oxygen species (ROS) following MRSA challenge, an effect independent of the angiotensin II AT1 receptor. Specifically, as compared to wild type mice (WT), there was a marked increase of superoxide generation (greater than 2-fold, p<0.0005) in NeuACE neutrophils following infection while ACE knockout neutrophils decreased superoxide production. Analysis of membrane p47-phox and p67-phox indicates that ACE increases NADPH oxidase activity but does not increase expression of these subunits. Increased ROS generation mediates the enhanced bacterial resistance of NeuACE mice as the enhanced resistance is lost with DPI inhibition. NeuACE granulocytes also have increased neutrophil extracellular trap formation (NET) and IL-1β release in response to MRSA. In a mouse model of chemotherapy-induced neutrophil depletion, transfusion of ACE overexpressing neutrophils was superior to WT neutrophils in treating MRSA infection. These data indicate a previously unknown function of ACE in neutrophil anti-bacterial defenses, and suggest caution in the treatment of certain individuals with ACE inhibitors. ACE overexpression in neutrophils may be useful in boosting the immune response to antibiotic resistance bacterial infection.

  • Submitted November 16, 2016.
  • Accepted May 15, 2017.