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Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature
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Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature
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Journal Article
Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature
2015
Overview
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.
Neutrophil extracellular traps (NETs) released by neutrophils trap pathogens but may also cause tissue damage. Here the authors show that during systemic
Staphylococcus aureus
infection NETs anchoring to the vasculature are only partially DNase-sensitive, advocating for better anti-NET therapies.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
Subject
/ 14/19
/ 14/34
/ 64/110
/ Animals
/ Deoxyribonucleases - metabolism
/ DNA
/ Extracellular Traps - immunology
/ Humanities and Social Sciences
/ Leukocyte Elastase - genetics
/ Leukocyte Elastase - metabolism
/ Liver
/ Male
/ Methicillin-Resistant Staphylococcus aureus
/ Mice
/ Science
/ Staphylococcal Infections - immunology
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