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

Nat Commun. 2015 Mar 26;6:6673. doi: 10.1038/ncomms7673.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteremia / immunology*
  • Bacteremia / metabolism
  • Deoxyribonucleases / metabolism
  • Extracellular Traps / immunology*
  • Hepatic Artery / immunology*
  • Hepatic Artery / metabolism
  • Hepatic Veins / immunology*
  • Hepatic Veins / metabolism
  • Histones / metabolism
  • Hydrolases / genetics
  • Kupffer Cells / immunology
  • Leukocyte Elastase / genetics*
  • Leukocyte Elastase / metabolism
  • Liver / blood supply
  • Liver / enzymology
  • Liver / immunology*
  • Liver / metabolism
  • Male
  • Methicillin-Resistant Staphylococcus aureus
  • Mice
  • Mice, Knockout
  • Neutrophil Infiltration
  • Protein-Arginine Deiminase Type 4
  • Staphylococcal Infections / immunology*
  • Staphylococcal Infections / metabolism
  • von Willebrand Factor / metabolism

Substances

  • Histones
  • von Willebrand Factor
  • Hydrolases
  • Deoxyribonucleases
  • Leukocyte Elastase
  • Protein-Arginine Deiminase Type 4
  • peptidylarginine deiminase 4, mouse