Clark, Stephen Robert ORCID: https://orcid.org/0000-0001-5907-9671, Coffey, Marcus Jonathan, McLean, Rhona Murray, Collins, Peter William ORCID: https://orcid.org/0000-0002-6410-1324, Lewis, Malcolm John, Cross, Andrew R. and O'Donnell, Valerie Bridget ORCID: https://orcid.org/0000-0003-4089-8460 2002. Characterization of nitric oxide consumption pathways by normal, chronic granulomatous disease and myeloperoxidase-deficient human neutrophils. The Journal of Immunology 169 (10) , pp. 5889-5896. |
Abstract
The detailed mechanisms by which acutely activated leukocytes metabolize NO and regulate its bioactivity are unknown. Therefore, healthy, chronic granulomatous disease (CGD) or myeloperoxidase (MPO)-deficient human neutrophils were examined for their ability to consume NO and attenuate its signaling. fMLP or PMA activation of healthy neutrophils caused NO consumption that was fully blocked by NADPH oxidase inhibition, and was absent in CGD neutrophils. Studies using MPO-deficient neutrophils, enzyme inhibitors, and reconstituted NADPH oxidase ruled out additional potential NO-consuming pathways, including Fenton chemistry, PGH synthase, lipoxygenase, or MPO. In particular, the inability of MPO to consume NO resulted from lack of H2O2 substrate since all superoxide (O2minusdu;) reacted to form peroxynitrite. For healthy or MPO-deficient cells, NO consumption rates were 2- to 4-fold greater than O2minusdu; generation, significantly faster than expected from 1:1 termination of NO with O2minusdu; Finally, fMLP or PMA-stimulated NO consumption fully blocked NO-dependent neutrophil cGMP synthesis. These data reveal NADPH oxidase as the central regulator of NO signaling in human leukocytes. In addition, they demonstrate an important functional difference between CGD and either normal or MPO-deficient human neutrophils, namely their inability to metabolize NO which will alter their ability to adhere and migrate in vivo.
Item Type: | Article |
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Date Type: | Publication |
Status: | Published |
Schools: | Medicine Systems Immunity Research Institute (SIURI) |
Publisher: | American Association of Immunologists |
ISSN: | 0022-1767 |
Last Modified: | 17 Oct 2022 08:27 |
URI: | https://orca.cardiff.ac.uk/id/eprint/197 |
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