Novel cell death program leads to neutrophil extracellular traps
Open accessAbstract
Neutrophil extracellular traps (NETs) are extracellular structures composed of chromatin and granule proteins that bind and kill microorganisms. We show that upon stimulation, the nuclei of neutrophils lose their shape, and the eu- and heterochromatin homogenize. Later, the nuclear envelope and the granule membranes disintegrate, allowing the mixing of NET components. Finally, the NETs are released as the cell membrane breaks. This cell death process is distinct from apoptosis and necrosis and depends on the generation of reactive oxygen species (ROS) by NADPH oxidase. Patients with chronic granulomatous disease carry mutations in NADPH oxidase and cannot activate this cell-death pathway or make NETs. This novel ROS-dependent death allows neutrophils to fulfill their antimicrobial function, even beyond their lifespan.
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Both NETotic cell death and NET extrusion in the absence of RCD rely on activity of NADPH oxidases.
“both NETotic cell death and NET extrusion in the absence of RCD appears to rely on the activity of NADPH oxidases [724, 736, 737].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [736]
This process culminates with extrusion of chromatin fibers intermixed with cytoplasmic and nuclear components, leading to plasma membrane rupture and RCD.
“This would culminate with the extrusion of chromatin fibers intermixed with cytoplasmic and nuclear components, ultimately leading to plasma membrane rupture and RCD [736].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [736]
NETotic cell death has been suggested to result from a signaling pathway involving RAF1, MAP2Ks, and ERK2, culminating with NADPH oxidase activation and ROS generation.
“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 [736]
An initial step in the intracellular signaling cascade in neutrophils that results in pathogen-induced NET formation is activation of the phagocytic NADPH oxidase (NOX2) enzyme complex.
“An initial step in the intracellular signaling cascade in neutrophils that results in pathogen-induced NET formation is activation of the phagocytic NADPH oxidase (NOX2) enzyme complex (24).”
From Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps (2016) · cites this paper as [24]
One type of NET formation requires NADPH oxidase activity and generally results in neutrophil lysis 2-4 hours after activation.
“One requires NADPH oxidase activity and generally results in neutrophil lysis 2-4 hours after activation (24), whereas another process occurs rapidly (5-60 min), independent of NADPH oxidase-activity, and leaves the neutrophil plasma membrane intact (26).”
From Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps (2016) · cites this paper as [24]
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- Authors
- Fuchs, T. A., Abed, U., Goosmann, C., Hurwitz, R., Schulze, I., Wahn, V., Weinrauch, Y., Brinkmann, V., & Zychlinsky, A.
- Affiliations
- New York University (US)
- 1Department for Cellular Microbiology
- Max Planck Institute for Infection Biology (DE)
- Charité – Universitätsmedizin Berlin (DE)
- 2Microscopy Core Facility,
- Corresponding author
- Zychlinsky, Arturo
- ORCID
- Venue
- The Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2007-01-08
- Volume
- 176
- Issue
- 2
- Pages
- 231-241
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2063942
- OpenAlex
- W2118217258
- Cited by
- 3,197
- References
- 38
- Citations by year
- 2026: 167 · 2025: 190 · 2024: 203 · 2023: 218 · 2022: 228 · 2021: 251 · 2020: 251 · 2019: 222 · 2018: 199 · 2017: 204 · 2016: 199 · 2015: 172 · 2014: 155 · 2013: 140 · 2012: 137
- FWCI
- 23.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- neutrophil extracellular traps, neutrophil cell death, reactive oxygen species, NADPH oxidase, chronic granulomatous disease, nuclear envelope breakdown, chromatin, neutrophil granules, antimicrobial defense, neutrophil lifespan
- MeSH terms
- Antibodies, Catalase, Cell Survival, Chromatin, Cytoplasmic Granules, Enzyme Inhibitors, Granulomatous Disease, Chronic, Humans, Hydrogen Peroxide, Immunity, Innate, Microscopy, Electron, Neutrophils, Nuclear Envelope, Onium Compounds, Phagocytosis, Staphylococcus aureus, Tetradecanoylphorbol Acetate, Vacuoles, Cell Death, Apoptosis, Reactive Oxygen Species, Neutrophil Activation, fas Receptor, NADPH Oxidases, Leukocyte Elastase
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