4.6 Article

Neutrophil extracellular traps and inflammasomes cooperatively promote venous thrombosis in mice

Journal

BLOOD ADVANCES
Volume 5, Issue 9, Pages 2319-2324

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ELSEVIER
DOI: 10.1182/bloodadvances.2020003377

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Funding

  1. British Heart Foundation [PG/18/46/33817]
  2. British Heart Foundation Senior Basic Science Research Fellowship [FS/19/30/34173]
  3. Henry Wellcome Fellowship [218649/Z/19/Z]
  4. Wellcome Trust [218649/Z/19/Z] Funding Source: Wellcome Trust

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The study shows a potential interaction between neutrophil extracellular traps (NETs) and inflammasomes in the development of DVT, which may support the formation of venous thrombosis through this mechanism.
Deep vein thrombosis (DVT) is linked to local inflammation. A role for both neutrophil extracellular traps (NETs) and the assembly of inflammasomes (leading to caspase1-dependent interleukin-1 beta 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.

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