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Abstract
Deep vein thrombosis (DVT) is linked to local inflammation. A role for both neutrophil extracellular traps (NETs) and the assembly of inflammasomes (leading to caspase-1-dependent interleukin-1b activation) in the development of DVT was recently suggested. However, no link between these 2 processes in the setting of thrombosis has been investigated. Here, we demonstrate that stimulation of neutrophils induced simultaneous formation of NETs and active caspase-1. Caspase-1 was largely associated with NETs, suggesting that secreted active caspase-1 requires NETs as an adhesive surface. NETs and their components, histones, promoted robust caspase-1 activation in platelets with the strongest effect exerted by histones 3/4. Murine DVT thrombi contained active caspase-1, which peaked at 6 hours when compared with 48-hour thrombi. Platelets constituted more than one-half of cells containing active caspase-1 in dissociated thrombi. Using intravital microscopy, we identified colocalized NETs and caspase-1 as well as platelet recruitment at the site of thrombosis. Pharmacological inhibition of caspase-1 strongly reduced DVT in mice, and thrombi that still formed contained no citrullinated histone 3, a marker of NETs. Taken together, these data demonstrate a cross-talk between NETs and inflammasomes both in vitro and in the DVT setting. This may be an important mechanism supporting thrombosis in veins.
Original language | English |
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Pages (from-to) | 2319–2324 |
Number of pages | 6 |
Journal | Blood Advances |
Volume | 5 |
Issue number | 9 |
DOIs | |
Publication status | Published - 3 May 2021 |
Bibliographical note
Funding Information:Acknowledgments This work was supported by a British Heart Foundation Project Grant (PG/18/46/33817) (A.B.). A.B. is supported by a British Heart Foundation Senior Basic Science Research Fellowship (FS/19/30/ 34173). A.O.K. is supported by a Henry Wellcome Fellowship (218649/Z/19/Z).
Publisher Copyright:
© 2021 by The American Society of Hematology
Keywords
- Animals
- Blood Platelets
- Extracellular Traps
- Inflammasomes
- Mice
- Neutrophils
- Venous Thrombosis
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