Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature
Open Access
- 26 March 2015
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 6 (1), 6673
- https://doi.org/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.This publication has 59 references indexed in Scilit:
- Traps and hyper inflammation – new ways that neutrophils promote or hinder survivalBritish Journal of Haematology, 2013
- NETosis: how vital is it?Blood, 2013
- Neutrophil recruitment and function in health and inflammationNature Reviews Immunology, 2013
- Intravascular Neutrophil Extracellular Traps Capture Bacteria from the Bloodstream during SepsisCell Host & Microbe, 2012
- The neutrophil in vascular inflammationNature Medicine, 2011
- Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular trapsThe Journal of cell biology, 2010
- PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular trapsThe Journal of Experimental Medicine, 2010
- Novel cell death program leads to neutrophil extracellular trapsThe Journal of cell biology, 2007
- CRIg: A Macrophage Complement Receptor Required for Phagocytosis of Circulating PathogensCell, 2006
- Neutrophil Extracellular Traps Kill BacteriaScience, 2004