A Novel Mechanism of Rapid Nuclear Neutrophil Extracellular Trap Formation in Response to Staphylococcus aureus
Abstract
Neutrophil extracellular traps (NETs) are webs of DNA covered with antimicrobial molecules that constitute a newly described killing mechanism in innate immune defense. Previous publications reported that NETs take up to 3–4 h to form via an oxidant-dependent event that requires lytic death of neutrophils. In this study, we describe neutrophils responding uniquely to Staphylococcus aureus via a novel process of NET formation that did not require neutrophil lysis or even breach of the plasma membrane. The multilobular nucleus rapidly became rounded and condensed. During this process, we observed the separation of the inner and outer nuclear membranes and budding of vesicles, and the separated membranes and vesicles were filled with nuclear DNA. The vesicles were extruded intact into the extracellular space where they ruptured, and the chromatin was released. This entire process occurred via a unique, very rapid (5–60 min), oxidant-independent mechanism. Mitochondrial DNA constituted very little if any of these NETs. They did have a limited amount of proteolytic activity and were able to kill S. aureus. With time, the nuclear envelope ruptured, and DNA filled the cytoplasm presumably for later lytic NET production, but this was distinct from the vesicular release mechanism. Panton–Valentine leukocidin, autolysin, and a lipase were identified in supernatants with NET-inducing activity, but Panton–Valentine leukocidin was the dominant NET inducer. We describe a new mechanism of NET release that is very rapid and contributes to trapping and killing of S. aureus.
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Of more than 50 evaluated neutrophils, none showed evidence of DNA-containing vesicles budding from the nucleus, the morphology typical for non-lytic NET-forming neutrophils.
“Of >50 evaluated neutrophils, none showed evidence of DNA-containing vesicles budding from the nucleus, the morphology described as typical for non-lytic NET-forming neutrophils (26).”
From Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps (2016) · cites this paper as [26]
Another type of NET formation occurs rapidly (5-60 min), is independent of NADPH oxidase activity, and leaves the neutrophil plasma membrane intact.
“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 [26]
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- Authors
- Pilsczek, F. H., Salina, D., Poon, K. K. H., Fahey, C., Yipp, B. G., Sibley, C. D., Robbins, S. M., Green, F. H. Y., Surette, M. G., Sugai, M., Bowden, M. G., Hussain, M., Zhang, K., & Kubes, P.
- Affiliations
- Snyder Institute of Infection, Immunity and Inflammation , Hiroshima ,
- Department of Oncology and Biochemistry and Molecular Biology , Hiroshima ,
- Hiroshima University (JP)
- Texas A&M University System (US)
- University Hospital Münster (DE)
- Department of Pathology and Laboratory Medicine , Hiroshima ,
- University of Calgary (CA)
- Corresponding author
- Salina, Davide
- Fahey, Candace
- Hussain, Muzaffar
- Kubes, Paul
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-12
- Volume
- 185
- Issue
- 12
- Pages
- 7413-7425
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2112543741
- Cited by
- 1,114
- References
- 48
- Citations by year
- 2026: 72 · 2025: 81 · 2024: 62 · 2023: 100 · 2022: 103 · 2021: 94 · 2020: 84 · 2019: 86 · 2018: 85 · 2017: 55 · 2016: 90 · 2015: 61 · 2014: 56 · 2013: 41 · 2012: 28
- FWCI
- 11.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- 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 › Genetics › Blood disorders and treatments
- Keywords
- neutrophil extracellular traps, Staphylococcus aureus, nuclear envelope rupture, Panton-Valentine leukocidin, autolysin, lipase, innate immune defense, bacterial killing, chromatin release
- MeSH terms
- Bacterial Toxins, Chromatin, Cytoplasm, DNA, Mitochondrial, Exotoxins, Humans, Immunity, Innate, Leukocidins, Neutrophils, Oxidation-Reduction, Staphylococcus aureus
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