Neutrophil extracellular trap cell death requires both autophagy and superoxide generation

By Q. Remijsen, T. Vanden Berghe, Ellen Wirawan, B. Asselbergh, E. Parthoens, R. Rycke, Sam Noppen, M. Delforge, J. Willems, Peter Vandenabeele. Cell Research, 2011

802 citations recorded by the source corpus.

Neutrophil extracellular traps (NETs) are extracellular chromatin structures that can trap and degrade microbes. They arise from neutrophils that have activated a cell death program called NET cell death, or NETosis. Activation of NETosis has been shown to involve NADPH oxidase activity, disintegration of the nuclear envelope and most granule membranes, decondensation of nuclear chromatin and formation of NETs. We report that in phorbol myristate acetate (PMA)-stimulated neutrophils, intracellular chromatin decondensation and NET formation follow autophagy and superoxide production, both of which are required to mediate PMA-induced NETosis and occur independently of each other. Neutrophils from patients with chronic granulomatous disease, which lack NADPH oxidase activity, still exhibit PMA-induced autophagy. Conversely, PMA-induced NADPH oxidase activity is not affected by pharmacological inhibition of autophagy. Interestingly, inhibition of either autophagy or NADPH oxidase prevents intracellular chromatin decondensation, which is essential for NETosis and NET formation, and results in cell death characterized by hallmarks of apoptosis. These results indicate that apoptosis might function as a backup program for NETosis when autophagy or NADPH oxidase activity is prevented.

Subfields: Immunology, Infectious Diseases, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f808ea3a4dfdc5a1c9dede2ee5a7cbdb8c108b35

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Guido Kroemer
2. L. Galluzzi
3. Simone Fulda
4. V. Brinkmann
5. I. Slaninová
6. Arturo Zychlinsky
7. Oliver Kepp
8. T. Vanden Berghe

In Infectious Diseases

1. V. Brinkmann
2. G. Núñez
3. Guido Kroemer
4. Douglas R. Green

In Molecular Biology

1. Guido Kroemer
2. L. Galluzzi
3. Douglas R. Green
4. Simone Fulda
5. Oliver Kepp
6. I. Slaninová
7. Peter Vandenabeele
8. Junying Yuan

Citations in the corpus

• Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality (2011, positive): “We recently found that formation of NETs by activated neutrophils requires not only NADPH-oxidasemediated superoxide production, but also autophagy.(12)”
• Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012 (2011, background): “responsible for the oxidative burst occurring during neutrophil activation) or autophagy.(160,162) Of note, ROS appear to be required but insufficient for netosis to occur, suggesting that”
• Neutrophils: Between Host Defence, Immune Modulation, and Tissue Injury (2015, background): “In addition to ROS, several other pathways have been reported to be involved in NET formation, such as peptidyl arginine deiminase (PAD) 4 [64], the Raf-MEK (mitogen-activated kinase/ERK kinase)-ERK (extracellular signalregulated kinase) pathway [65] and autophagy [66].”
• Neutrophil Extracellular Traps Directly Induce Epithelial and Endothelial Cell Death: A Predominant Role of Histones (2012, background): “PMA, at this concentration, does not promote apoptosis or necrosis; rather, it induces typical features of NETosis [4,40–44].”
• Diverse stimuli engage different neutrophil extracellular trap pathways (2017, background): “…mechanisms of neutrophil cell death have been studied in detail and as such the data presented here can be included in the body of evidence that NETosis is in fact a distinct cell death mechanism utilised to aid in pathogen killing by neutrophils (Fuchs et al., 2007; Remijsen et al., 2011b, 2011a).”
• Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2012, positive): “Moreover, autophagy regulates an important neutrophil function, the generation of neutrophil extracellular traps (NETs).(1024,1032)”
• SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx (2015, methodology): “The plate reader assay is routinely used for monitoring NET DNA release (4, 6, 17), and it detects extracellular NETs with a cell impermeable, extracellular DNA dye Sytox Green.”
• The Multifaceted Functions of Neutrophils (2013, background): “ROS may inactivate intracellular caspases to inhibit apoptosis and induce autophagy, which would promote the breakdown of cellular membranes during NETosis (121).”