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

Abstract

Angiotensin-converting enzyme (ACE) inhibitors are widely used to reduce blood pressure. Here, we examined if an 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 (MRSA). In contrast, mice overexpressing ACE in neutrophils (Neu mice) have increased resistance to MRSA and better in vitro killing of MRSA, , and 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 with wild-type (WT) mice, there was a marked increase of superoxide generation (>twofold, < .0005) in Neu neutrophils following infection, whereas ACE knockout neutrophils decreased superoxide production. Analysis of membrane p47-phox and p67-phox indicates that ACE increases reduced NAD phosphate oxidase activity but does not increase expression of these subunits. Increased ROS generation mediates the enhanced bacterial resistance of Neu mice because the enhanced resistance is lost with DPI (an inhibitor of ROS production by flavoenzymes) inhibition. Neu granulocytes also have increased neutrophil extracellular trap formation and interleukin-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 antibacterial 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-resistant bacterial infection.

Angiotensin-converting enzyme in innate and adaptive immunity

“…WT neutrophils increase ACE expression levels in response to an MRSA-mediated immune challenge 68 . To study the effect of neutrophil ACE overexpression in response to bacterial infection, we generated a transgenic mouse model (NeuACE mice) in which so-called NeuACE neutrophils overexpress ACE by 12-fold to 18-fold compared with cells from WT mice 68 (FIG. 4a).…”

“…4b–d). This phenotype is dependent on neutrophil function, as neutrophil elimination with anti-neutrophil antisera eliminates the differences in both lesion size and bacterial counts between NeuACE and WT animals 68 . In addition, NeuACE neutrophils kill bacteria more efficiently than do WT neutrophils in vitro.…”

“…In addition, NeuACE neutrophils kill bacteria more efficiently than do WT neutrophils in vitro. By contrast, ACE-deficient neutrophils are significantly less effective at killing bacteria than are WT cells in vitro and in vivo: for example, at the end of an in vitro whole-blood killing assay, bacterial counts in samples with ACE-deficient neutrophils were 6-fold greater than in those using WT neutrophils and 30-fold greater than in those using NeuACE neutrophils 68 . These data suggest that a direct relationship between ACE production in neutrophils and the ability to kill bacteria exists.…”

“…O 2 − is then converted to hydrogen peroxide (H 2 O 2 ) and hypochlorous acid (HClO), which are bactericidal 69 . To evaluate whether ACE has a role in O 2 − production, we challenged neutrophils from NeuACE and WT mice with MRSA and found that, although both cell populations had increased O 2 − production, levels from NeuACE cells were >2-fold higher than those from WT cells 68 . By contrast, O 2 − production by ACE-deficient neutrophils was ~50% that of WT neutrophils 68 .…”

Targeting fundamental pathways to disrupt Staphylococcus aureus survival: clinical implications of recent discoveries

“…An alternative approach to increase oxidative killing of S. aureus is to boost the oxidative function of host phagocytes. In neutrophils, increasing angiotensin-converting enzyme expression has been shown to boost oxidative killing (120). Targeting both bacterial antioxidant defense and boosting host oxidative function represents a potential synergistic approach to combat S. aureus.…”