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Nature 416, 291-297 (21 March 2002) | doi:10.1038/416291a; Received 12 December 2001; Accepted 23 January 2002

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

Emer P. Reeves1,2, Hui Lu1,2, Hugues Lortat Jacobs3, Carlo G. M. Messina1, Steve Bolsover4, Giorgio Gabella5, Eric O. Potma6, Alice Warley7, Jürgen Roes8 & Anthony W. Segal1

  1. Centre for Molecular Medicine, University College London, 5 University Street, London WC1E 6JJ, UK
  2. Centre for Molecular Medicine, Department of Physiology, University College London, 5 University Street, London WC1E 6JJ, UK
  3. Centre for Molecular Medicine, Department of Anatomy , University College London, 5 University Street, London WC1E 6JJ, UK
  4. Windeyer Institute of Medical Sciences, University College London, 5 University Street, London WC1E 6JJ, UK
  5. Institut de Biologie Structurale, 41 rue Horowitz, 38027 Grenoble, France
  6. Ultrafast Laser and Spectroscopy Laboratory, Materials Science Centre, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
  7. Rayne Institute, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK
  8. These authors contributed equally to this work.

Correspondence to: Anthony W. Segal1 Correspondence and requests for materials should be addressed to A.W.S. (e-mail: Email: rmhaase@ucl.ac.uk).

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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.

  1. Centre for Molecular Medicine, University College London, 5 University Street, London WC1E 6JJ, UK
  2. Centre for Molecular Medicine, Department of Physiology, University College London, 5 University Street, London WC1E 6JJ, UK
  3. Centre for Molecular Medicine, Department of Anatomy , University College London, 5 University Street, London WC1E 6JJ, UK
  4. Windeyer Institute of Medical Sciences, University College London, 5 University Street, London WC1E 6JJ, UK
  5. Institut de Biologie Structurale, 41 rue Horowitz, 38027 Grenoble, France
  6. Ultrafast Laser and Spectroscopy Laboratory, Materials Science Centre, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
  7. Rayne Institute, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK
  8. These authors contributed equally to this work.

Correspondence to: Anthony W. Segal1 Correspondence and requests for materials should be addressed to A.W.S. (e-mail: Email: rmhaase@ucl.ac.uk).