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Neutrophil extracellular trap cell death requires both autophagy and superoxide generation
Open accessAbstract
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.
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“NETotic cell death has been suggested to result from a signaling pathway that involves Raf-1 proto-oncogene, serine/threonine kinase (RAF1), mitogen-activated protein kinase kinases (MAP2Ks), and ERK2, culminating with NADPH oxidase activation and consequent ROS generation [736, 738, 739].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [739]
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Metadata
- Authors
- Remijsen, Q., Berghe, T. V., Wirawan, E., Asselbergh, B., Parthoens, E., De Rycke, R., Noppen, S., Delforge, M., Willems, J., & Vandenabeele, P.
- Affiliations
- KU Leuven (BE)
- Ghent University (BE)
- Universitair Ziekenhuis Leuven (BE)
- Corresponding author
- Willems, Jean
- Vandenabeele, Peter
- Venue
- Cell Research
- Published
- 2010-11-09
- Volume
- 21
- Issue
- 2
- Pages
- 290-304
- ISSN
- 1001-0602 (ISSN-L)
- 1748-7838
- PMC
- PMC3193439
- OpenAlex
- W2091512988
- Cited by
- 818
- References
- 51
- Citations by year
- 2026: 32 · 2025: 58 · 2024: 50 · 2023: 54 · 2022: 48 · 2021: 68 · 2020: 57 · 2019: 87 · 2018: 56 · 2017: 73 · 2016: 62 · 2015: 49 · 2014: 40 · 2013: 39 · 2012: 31
- FWCI
- 11.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- www.springer.com/tdm (tdm)
- Locations
- Cell Research (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Funders
- European Commission (200767)
- Universiteit Gent (01M00709)
- Vlaams Instituut voor Biotechnologie (BOF09/01M00709)
- Vlaamse regering (BOF09/01M00709)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
- Keywords
- neutrophil extracellular traps, NETosis, autophagy, superoxide, NADPH oxidase, chromatin decondensation, neutrophil cell death, apoptosis, chronic granulomatous disease, phorbol myristate acetate, innate immunity
- MeSH terms
- NADPH Oxidase 2, Autophagy, Granulomatous Disease, Chronic, Humans, Membrane Glycoproteins, NADH, NADPH Oxidoreductases, Neutrophils, Superoxides, Tetradecanoylphorbol Acetate, Apoptosis, NADPH Oxidases, Chromatin Assembly and Disassembly
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