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

Emer P. Reeves, Hui Lu, Hugues Lortat Jacobs, Carlo G. M. Messina, Steve Bolsover, Giorgio Gabella, Eric O. Potma, Alice Warley, Jürgen Roes and Anthony W. Segal ()
Additional contact information
Emer P. Reeves: University College London
Hui Lu: University College London
Hugues Lortat Jacobs: Institut de Biologie Structurale
Carlo G. M. Messina: University College London
Steve Bolsover: University College London
Giorgio Gabella: University College London
Eric O. Potma: Ultrafast Laser and Spectroscopy Laboratory, Materials Science Centre, University of Groningen
Alice Warley: Rayne Institute, St Thomas' Hospital
Jürgen Roes: University College London
Anthony W. Segal: University College London

Nature, 2002, vol. 416, issue 6878, 291-297

Abstract: 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.

Date: 2002
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DOI: 10.1038/416291a

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