title: Killing activity of neutrophils is mediated through activation of proteases by K+ flux.
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.
authors.affiliation: Centre for Molecular Medicine, University College London, 5 University Street, London WC1E 6JJ, UK.
authors.forename: Emer P
authors.initials: EP
authors.lastname: Reeves
authors.forename: Hui
authors.initials: H
authors.lastname: Lu
authors.forename: Hugues Lortat
authors.initials: HL
authors.lastname: Jacobs
authors.forename: Carlo G M
authors.initials: CG
authors.lastname: Messina
authors.forename: Steve
authors.initials: S
authors.lastname: Bolsover
authors.forename: Giorgio
authors.initials: G
authors.lastname: Gabella
authors.forename: Eric O
authors.initials: EO
authors.lastname: Potma
authors.forename: Alice
authors.initials: A
authors.lastname: Warley
authors.forename: Jürgen
authors.initials: J
authors.lastname: Roes
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Segal
mesh_terms: D000818:Animals; D002177:Candidiasis / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004594:Electrophysiology; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D009504:Neutrophils / Q000276:immunology*; D010100:Oxygen / Q000378:metabolism; D009195:Peroxidase / Q000172:deficiency / Q000378:metabolism*; D010588:Phagosomes / Q000502:physiology; D011188:Potassium / Q000378:metabolism*; D013203:Staphylococcal Infections / Q000276:immunology; D013481:Superoxides / Q000378:metabolism
chemical_list: D013481:Superoxides; D009195:Peroxidase; D011188:Potassium; D010100:Oxygen