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Angiotensin converting enzyme enhances the oxidative response and bactericidal activity of neutrophils
Author(s) -
Bernstein Kenneth E,
Khan Zakir,
Shen Xiao Z,
Bernstein Ellen A,
Giani Jorge F,
Eriguchi Masahiro,
Zhao Tuantuan V,
GonzalezVillalobos Romer A,
Fuchs Sebastien,
Liu George Y
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.854.3
Subject(s) - nadph oxidase , neutrophil extracellular traps , angiotensin ii , superoxide , reactive oxygen species , chemistry , inflammation , oxidase test , bone marrow , pharmacology , microbiology and biotechnology , immunology , biology , receptor , enzyme , biochemistry
We studied the role of angiotensin converting enzyme (ACE) in neutrophils. ACE knockout (KO) mice or mice treated with an ACE inhibitor were more susceptible to bacterial infection by methicillin‐resistant S. aureus (MRSA). Specifically, KO mice have larger skin lesions (4‐fold) and more bacteria per lesion (3.3‐fold) compared to wild type (WT). WT mice transplanted with ACE KO bone marrow are also significantly more susceptible than WT mice transplanted with WT bone marrow. In contrast, mice over expressing ACE in neutrophils (Neu ACE mice) have increased resistance to MRSA (smaller lesions, less bacteria), 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 WT mice, there was a marked increase of SOD inhibitable superoxide generation (greater than 2‐fold, p<0.0005) in Neu ACE neutrophils following MRSA infection. These functional studies and the increased association of cytosolic subunits of NADPH oxidase (p47‐phox, p67‐phox) with membrane gp91‐phox indicate that ACE directly affects NADPH oxidase activity. Myloperoxidase activity in neutrophils was equivalent to that of WT mice. Increased ROS generation mediates the enhanced bacterial resistance of Neu ACE mice as the enhanced resistance is lost with DPI inhibition or with ACE inhibitors. Neu ACE 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. Support or Funding Information NIH grants R01DK098382 (KEB), R21AI114965 (KEB), and R03DK101592 (RAGV).