Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature

Elzbieta Kolaczkowska, Craig N. Jenne, Bas G. J. Surewaard, Ajitha Thanabalasuriar, Woo-Yong Lee, Maria-Jesus Sanz, Kerri Mowen, Ghislain Opdenakker and Paul Kubes ()
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Elzbieta Kolaczkowska: Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3280 Hospital Drive N.W.
Craig N. Jenne: Immunology and Infectious Diseases, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3280 Hospital Drive N.W.
Bas G. J. Surewaard: Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3280 Hospital Drive N.W.
Ajitha Thanabalasuriar: Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3280 Hospital Drive N.W.
Woo-Yong Lee: Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3280 Hospital Drive N.W.
Maria-Jesus Sanz: Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3280 Hospital Drive N.W.
Kerri Mowen: Scripps Research Institute La Jolla, 10550 North Torrey Pines Road
Ghislain Opdenakker: Laboratory of Immunobiology, Rega Institute for Medical Research, KU Leuven - University of Leuven, Minderbroedersstraat 10 blok x - bus 1030
Paul Kubes: Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3280 Hospital Drive N.W.

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract Neutrophil extracellular traps (NETs) composed of DNA decorated with histones and proteases trap and kill bacteria but also injure host tissue. Here we show that during a bloodstream infection with methicillin-resistant Staphylococcus aureus, the majority of bacteria are sequestered immediately by hepatic Kupffer cells, resulting in transient increases in liver enzymes, focal ischaemic areas and a robust neutrophil infiltration into the liver. The neutrophils release NETs into the liver vasculature, which remain anchored to the vascular wall via von Willebrand factor and reveal significant neutrophil elastase (NE) proteolytic activity. Importantly, DNase although very effective at DNA removal, and somewhat effective at inhibiting NE proteolytic activity, fails to remove the majority of histones from the vessel wall and only partly reduces injury. By contrast, inhibition of NET production as modelled by PAD4-deficiency, or prevention of NET formation and proteolytic activity as modelled in NE−/− mice prevent collateral host tissue damage.

Date: 2015
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DOI: 10.1038/ncomms7673

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