title: Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature.
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.
authors: 1] Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3280 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1 [2] Department of Evolutionary Immunology, Institute of Zoology, Jagiellonian University, ul. Gronostajowa 9, 30-387 Krakow, Poland [3] Laboratory of Immunobiology, Rega Institute for Medical Research, KU Leuven - University of Leuven, Minderbroedersstraat 10 blok x - bus 1030, 3000 Leuven, Belgium.
authors: Elzbieta
authors: E
authors: Kolaczkowska
authors: Department of Microbiology, Immunology and Infectious Diseases, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3280 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1.
authors: Craig N
authors: CN
authors: Jenne
authors: Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3280 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1.
authors: Bas G J
authors: BG
authors: Surewaard
authors: Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3280 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1.
authors: Ajitha
authors: A
authors: Thanabalasuriar
authors: Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3280 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1.
authors: Woo-Yong
authors: WY
authors: Lee
authors: 1] Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3280 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1 [2] Department of Pharmacology, Faculty of Medicine, University of Valencia, Av. Blasco Ibañez 15, 46010 Valencia, Spain.
authors: Maria-Jesus
authors: MJ
authors: Sanz
authors: 1] Department of Chemical Physiology, Scripps Research Institute La Jolla, 10550 North Torrey Pines Road La Jolla, 92037 California, USA [2] Department Immunology and Microbial Sciences, Scripps Research Institute La Jolla, 10550 North Torrey Pines Road La Jolla, 92037 California, USA.
authors: Kerri
authors: K
authors: Mowen
authors: Laboratory of Immunobiology, Rega Institute for Medical Research, KU Leuven - University of Leuven, Minderbroedersstraat 10 blok x - bus 1030, 3000 Leuven, Belgium.
authors: Ghislain
authors: G
authors: Opdenakker
authors: Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3280 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1.
authors: Paul
authors: P
authors: Kubes
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000276:immunology* / Q000378:metabolism; D003851:Deoxyribonucleases / Q000378:metabolism; D065206:Extracellular Traps / Q000276:immunology*; D006499:Hepatic Artery / Q000276:immunology* / Q000378:metabolism; D006503:Hepatic Veins / Q000276:immunology* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006867:Hydrolases / Q000235:genetics; D007728:Kupffer Cells / Q000276:immunology; D019272:Leukocyte Elastase / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D000080002:Protein-Arginine Deiminase Type 4; D013203:Staphylococcal Infections / Q000276:immunology* / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D006657:Histones; D014841:von Willebrand Factor; D006867:Hydrolases; D003851:Deoxyribonucleases; D019272:Leukocyte Elastase; D000080002:Protein-Arginine Deiminase Type 4; C552151:peptidylarginine deiminase 4, mouse