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The NADPH Oxidase and Microbial Killing by Neutrophils, With a Particular Emphasis on the Proposed Antimicrobial Role of Myeloperoxidase within the Phagocytic Vacuole

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  • Authors: Adam P. Levine1, Anthony W. Segal2
  • Editor: Siamon Gordon3
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Division of Medicine, University College London, London WC1E 6JF, United Kingdom; 2: Division of Medicine, University College London, London WC1E 6JF, United Kingdom; 3: Oxford University, Oxford, United Kingdom
    • Source: microbiolspec July 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0018-2015
  • Received 13 August 2015 Accepted 26 October 2015 Published 08 July 2016
  • Anthony W. Segal, [email protected]
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  • Abstract:

    This review is devoted to a consideration of the way in which the NADPH oxidase of neutrophils, NOX2, functions to enable the efficient killing of bacteria and fungi. It includes a critical examination of the current dogma that its primary purpose is the generation of hydrogen peroxide as substrate for myeloperoxidase-catalyzed generation of hypochlorite. Instead, it is demonstrated that NADPH oxidase functions to optimize the ionic and pH conditions within the vacuole for the solubilization and optimal activity of the proteins released into this compartment from the cytoplasmic granules, which kill and digest the microbes. The general role of other NOX systems as electrochemical generators to alter the pH and ionic composition in compartments on either side of a membrane in plants and animals will also be examined.

  • Citation: Levine A, Segal A. 2016. The NADPH Oxidase and Microbial Killing by Neutrophils, With a Particular Emphasis on the Proposed Antimicrobial Role of Myeloperoxidase within the Phagocytic Vacuole. Microbiol Spectrum 4(4):MCHD-0018-2015. doi:10.1128/microbiolspec.MCHD-0018-2015.

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/content/journal/microbiolspec/10.1128/microbiolspec.MCHD-0018-2015
2016-07-08
2020-08-07

Abstract:

This review is devoted to a consideration of the way in which the NADPH oxidase of neutrophils, NOX2, functions to enable the efficient killing of bacteria and fungi. It includes a critical examination of the current dogma that its primary purpose is the generation of hydrogen peroxide as substrate for myeloperoxidase-catalyzed generation of hypochlorite. Instead, it is demonstrated that NADPH oxidase functions to optimize the ionic and pH conditions within the vacuole for the solubilization and optimal activity of the proteins released into this compartment from the cytoplasmic granules, which kill and digest the microbes. The general role of other NOX systems as electrochemical generators to alter the pH and ionic composition in compartments on either side of a membrane in plants and animals will also be examined.

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The NADPH Oxidase and Microbial Killing by Neutrophils, With a Particular Emphasis on the Proposed Antimicrobial Role of Myeloperoxidase within the Phagocytic Vacuole
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Citation: Levine A, Segal A. 2016. The nadph oxidase and microbial killing by neutrophils, with a particular emphasis on the proposed antimicrobial role of myeloperoxidase within the phagocytic vacuole. microbiolspec 4(4): doi:10.1128/microbiolspec.MCHD-0018-2015
/content/microbiolspec/10.1128/microbiolspec.MCHD-0018-2015.fig1
FIGURE 1

Time courses of changes in vacuolar pH in human and and wild-type (WT) mouse neutrophils phagocytosing SNARF-labeled . Reprinted from reference 40 , with permission.

microbiolspec/4/4/MCHD-0018-2015-fig1_thmb.gif
microbiolspec/4/4/MCHD-0018-2015-fig1.gif
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FIGURE 1

Time courses of changes in vacuolar pH in human and and wild-type (WT) mouse neutrophils phagocytosing SNARF-labeled . Reprinted from reference 40 , with permission.

Source: microbiolspec July 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0018-2015
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FIGURE 2

Schematic representation of the neutrophil phagocytic vacuole showing the consequences of electron transport by NOX2 onto oxygen. The proposed ion fluxes that might be required to compensate the movement of charge across the phagocytic membrane together with modulators of ion fluxes are shown. CCCP, carbonyl cyanide m-chlorophenyl hydrazone; NHE, sodium proton exchanger. Reprinted from reference 40 , with permission.

microbiolspec/4/4/MCHD-0018-2015-fig2_thmb.gif
microbiolspec/4/4/MCHD-0018-2015-fig2.gif
Image of FIGURE 2

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FIGURE 2

Schematic representation of the neutrophil phagocytic vacuole showing the consequences of electron transport by NOX2 onto oxygen. The proposed ion fluxes that might be required to compensate the movement of charge across the phagocytic membrane together with modulators of ion fluxes are shown. CCCP, carbonyl cyanide m-chlorophenyl hydrazone; NHE, sodium proton exchanger. Reprinted from reference 40 , with permission.

Source: microbiolspec July 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0018-2015
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/content/microbiolspec/10.1128/microbiolspec.MCHD-0018-2015.fig3
FIGURE 3

The effect of variations in pH on peroxidatic (TMB and o-Dianisidine) and chlorinating monochlorodimedone (MCD) activities of MPO and on the protease activities of cathepsin G and of elastase are shown. TMB, tetramethylbenzidine. From Levine et al. ( 40 ).

microbiolspec/4/4/MCHD-0018-2015-fig3_thmb.gif
microbiolspec/4/4/MCHD-0018-2015-fig3.gif
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FIGURE 3

The effect of variations in pH on peroxidatic (TMB and o-Dianisidine) and chlorinating monochlorodimedone (MCD) activities of MPO and on the protease activities of cathepsin G and of elastase are shown. TMB, tetramethylbenzidine. From Levine et al. ( 40 ).

Source: microbiolspec July 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0018-2015
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