Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood
Abstract
It has been known for many years that neutrophils and platelets participate in the pathogenesis of severe sepsis, but the inter-relationship between these players is completely unknown. We report several cellular events that led to enhanced trapping of bacteria in blood vessels: platelet TLR4 detected TLR4 ligands in blood and induced platelet binding to adherent neutrophils. This led to robust neutrophil activation and formation of neutrophil extracellular traps (NETs). Plasma from severely septic humans also induced TLR4-dependent platelet-neutrophil interactions, leading to the production of NETs. The NETs retained their integrity under flow conditions and ensnared bacteria within the vasculature. The entire event occurred primarily in the liver sinusoids and pulmonary capillaries, where NETs have the greatest capacity for bacterial trapping. We propose that platelet TLR4 is a threshold switch for this new bacterial trapping mechanism in severe sepsis.
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NET extrusion per se does not necessarily result in cellular lysis.
“NET extrusion per se does not necessarily result in cellular lysis [722, 724, 735].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [722]
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- Authors
- Clark, S. R., Ma, A. C., Tavener, S. A., McDonald, B., Goodarzi, Z., Kelly, M. M., Patel, K. D., Chakrabarti, S., McAvoy, E., Sinclair, G. D., Keys, E. M., Allen-Vercoe, E., DeVinney, R., Doig, C. J., Green, F. H. Y., & Kubes, P.
- Affiliations
- University of Calgary (CA)
- Corresponding author
- Kubes, Paul
- ORCID
- Venue
- Nature Medicine
- Published
- 2007-03-25
- Volume
- 13
- Issue
- 4
- Pages
- 463-469
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1986282241
- Cited by
- 2,309
- References
- 38
- Citations by year
- 2026: 100 · 2025: 136 · 2024: 104 · 2023: 152 · 2022: 200 · 2021: 189 · 2020: 167 · 2019: 175 · 2018: 137 · 2017: 146 · 2016: 124 · 2015: 131 · 2014: 119 · 2013: 112 · 2012: 105
- FWCI
- 17.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Keywords
- neutrophil extracellular traps, sepsis, neutrophil-platelet interaction, bacterial trapping, neutrophil activation, liver sinusoids, pulmonary capillaries, sepsis pathogenesis, threshold switches
- MeSH terms
- Alanine Transaminase, Animals, Bacteria, Blood Platelets, Epithelium, Humans, Lipopolysaccharides, Liver, Neutrophils, Sepsis, Toll-Like Receptor 4, Mice
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