Killing activity of neutrophils is mediated through activation of proteases by K+ flux

Reeves, Emer P.; Lu, Hui; Jacobs, Hugues Lortat; Messina, Carlo G. M.; Bolsover, Steve; Gabella, Giorgio; Potma, Eric O.; Warley, Alice; Roes, Jürgen; Segal, Anthony W.

doi:10.1038/416291a

Cited by 1,153Neutrophil, Myeloperoxidase and Oxidative MechanismsAntimicrobial Peptides and ActivitiesProtease and Inhibitor Mechanisms

Killing activity of neutrophils is mediated through activation of proteases by K+ flux

Reeves, Emer P., Lu, Hui, Jacobs, Hugues Lortat, Messina, Carlo G. M., Bolsover, Steve, Gabella, Giorgio, Potma, Eric O., Warley, Alice +2 more·2002·Nature

DOI 10.1038/416291a

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Abstract

According to the hitherto accepted view, neutrophils kill ingested microorganisms by subjecting them to high concentrations of highly toxic reactive oxygen species (ROS) and bringing about myeloperoxidase-catalysed halogenation. We show here that this simple scheme, which for many years has served as a satisfactory working hypothesis, is inadequate. We find that mice made deficient in neutrophil-granule proteases but normal in respect of superoxide production and iodinating capacity, are unable to resist staphylococcal and candidal infections. We also show that activation provokes the influx of an enormous concentration of ROS into the endocytic vacuole. The resulting accumulation of anionic charge is compensated for by a surge of K+ ions that cross the membrane in a pH-dependent manner. The consequent rise in ionic strength engenders the release of cationic granule proteins, including elastase and cathepsin G, from the anionic sulphated proteoglycan matrix. We show that it is the proteases, thus activated, that are primarily responsible for the destruction of the bacteria.

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O2− produced in phagolysosomes indirectly activates proteases.
“The O 2 ⅐Ϫ produced in phagolysosomes indirectly activates proteases (Reeves et al., 2002)”
From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Reeves et al., 2002

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Self-citation

Authors: Reeves, E. P., Lu, H., Jacobs, H. L., Messina, C. G. M., Bolsover, S., Gabella, G., Potma, E. O., Warley, A., Roes, J., & Segal, A. W.
Affiliations: University College London (GB)
University of Groningen (NL)
St Thomas' Hospital (GB)
Corresponding author: Segal, Anthony W.
ORCID: Reeves, Emer P.
Lu, Hui
Gabella, Giorgio
Potma, Eric O.
Roes, Jürgen
Segal, Anthony W.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2002-03
Volume: 416
Issue: 6878
Pages: 291-297
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/416291a
OpenAlex: W2084814184
Cited by: 1,153
References: 0
Citations by year: 2026: 17 · 2025: 25 · 2024: 24 · 2023: 24 · 2022: 26 · 2021: 33 · 2020: 39 · 2019: 35 · 2018: 41 · 2017: 44 · 2016: 42 · 2015: 41 · 2014: 63 · 2013: 47 · 2012: 54
FWCI: 23.03
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
UCL Discovery (University College London) (submittedVersion)
Research Portal (King's College London) (submittedVersion)
Research Explorer (The University of Manchester) (submittedVersion)
University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords: neutrophil killing, potassium influx, reactive oxygen species, endocytic vacuoles, elastase, cathepsin G, proteoglycan matrix, myeloperoxidase, staphylococcal infections, candidal infection, superoxide, phagocytosis
MeSH terms: Animals, Candidiasis, Cytotoxicity, Immunologic, Electrophysiology, Enzyme Activation, Humans, Peroxidase, Neutrophils, Oxygen, Phagosomes, Potassium, Staphylococcal Infections, Superoxides, Mice

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Killing activity of neutrophils is mediated through activation of proteases by K+ flux

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