Killing activity of neutrophils is mediated through activation of proteases by K+ flux.
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.
Reeves
Emer P
EP
Centre for Molecular Medicine, University College London, 5 University Street, London WC1E 6JJ, UK.
Lu
Hui
H
Jacobs
Hugues Lortat
HL
Messina
Carlo G M
CG
Bolsover
Steve
S
Gabella
Giorgio
G
Potma
Eric O
EO
Warley
Alice
A
Roes
Jürgen
J
Segal
Anthony W
AW
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
D013481:Superoxides; D009195:Peroxidase; D011188:Potassium; D010100:Oxygen