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Alkalinity of neutrophil phagocytic vacuoles is modulated by HVCN1 and has consequences for myeloperoxidase activity.

Levine AP, Duchen MR, de Villiers S, Rich PR, Segal AW - PLoS ONE (2015)

Bottom Line: Activity of the oxidase requires that charge movements across the vacuolar membrane are balanced.In human cells, the vacuolar pH rose to ~9, and the cytosol acidified slightly.Conditions in the vacuole are optimal for bacterial killing by the neutral proteases, cathepsin G and elastase, and not by myeloperoxidase, activity of which was unphysiologically low at alkaline pH.

View Article: PubMed Central - PubMed

Affiliation: Division of Medicine, University College London, London, United Kingdom.

ABSTRACT
The NADPH oxidase of neutrophils, essential for innate immunity, passes electrons across the phagocytic membrane to form superoxide in the phagocytic vacuole. Activity of the oxidase requires that charge movements across the vacuolar membrane are balanced. Using the pH indicator SNARF, we measured changes in pH in the phagocytic vacuole and cytosol of neutrophils. In human cells, the vacuolar pH rose to ~9, and the cytosol acidified slightly. By contrast, in Hvcn1 knock out mouse neutrophils, the vacuolar pH rose above 11, vacuoles swelled, and the cytosol acidified excessively, demonstrating that ordinarily this channel plays an important role in charge compensation. Proton extrusion was not diminished in Hvcn1-/- mouse neutrophils arguing against its role in maintaining pH homeostasis across the plasma membrane. Conditions in the vacuole are optimal for bacterial killing by the neutral proteases, cathepsin G and elastase, and not by myeloperoxidase, activity of which was unphysiologically low at alkaline pH.

No MeSH data available.


Related in: MedlinePlus

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.
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pone.0125906.g001: 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.

Mentions: Neutrophils that encounter a bacterium or fungus engulf it into a phagocytic vacuole of invaginated plasma membrane, into which cytoplasmic granules release their contents of potentially lethal enzymes (Fig 1). These processes are associated with a burst of non-mitochondrial respiration in which electrons are passed across the membrane of the vacuole by an NADPH oxidase, NOX2, that generates superoxide [1]. This electron transport is essential for efficient killing of the microbes as evidenced by the severe immunodeficiency syndrome of Chronic Granulomatous Disease (CGD) in which the function of NOX2 is absent or compromised [2].


Alkalinity of neutrophil phagocytic vacuoles is modulated by HVCN1 and has consequences for myeloperoxidase activity.

Levine AP, Duchen MR, de Villiers S, Rich PR, Segal AW - PLoS ONE (2015)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401748&req=5

pone.0125906.g001: 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.
Mentions: Neutrophils that encounter a bacterium or fungus engulf it into a phagocytic vacuole of invaginated plasma membrane, into which cytoplasmic granules release their contents of potentially lethal enzymes (Fig 1). These processes are associated with a burst of non-mitochondrial respiration in which electrons are passed across the membrane of the vacuole by an NADPH oxidase, NOX2, that generates superoxide [1]. This electron transport is essential for efficient killing of the microbes as evidenced by the severe immunodeficiency syndrome of Chronic Granulomatous Disease (CGD) in which the function of NOX2 is absent or compromised [2].

Bottom Line: Activity of the oxidase requires that charge movements across the vacuolar membrane are balanced.In human cells, the vacuolar pH rose to ~9, and the cytosol acidified slightly.Conditions in the vacuole are optimal for bacterial killing by the neutral proteases, cathepsin G and elastase, and not by myeloperoxidase, activity of which was unphysiologically low at alkaline pH.

View Article: PubMed Central - PubMed

Affiliation: Division of Medicine, University College London, London, United Kingdom.

ABSTRACT
The NADPH oxidase of neutrophils, essential for innate immunity, passes electrons across the phagocytic membrane to form superoxide in the phagocytic vacuole. Activity of the oxidase requires that charge movements across the vacuolar membrane are balanced. Using the pH indicator SNARF, we measured changes in pH in the phagocytic vacuole and cytosol of neutrophils. In human cells, the vacuolar pH rose to ~9, and the cytosol acidified slightly. By contrast, in Hvcn1 knock out mouse neutrophils, the vacuolar pH rose above 11, vacuoles swelled, and the cytosol acidified excessively, demonstrating that ordinarily this channel plays an important role in charge compensation. Proton extrusion was not diminished in Hvcn1-/- mouse neutrophils arguing against its role in maintaining pH homeostasis across the plasma membrane. Conditions in the vacuole are optimal for bacterial killing by the neutral proteases, cathepsin G and elastase, and not by myeloperoxidase, activity of which was unphysiologically low at alkaline pH.

No MeSH data available.


Related in: MedlinePlus