Neutrophil extracellular traps and inflammasomes cooperatively promote venous thrombosis in mice

Joana Campos, Tatyana Ponomaryov, Alexandra De Prendergast, Katie Whitworth, Christopher Smith, Abdullah Khan, Dean Kavanagh, Alexander Brill

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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 languageEnglish
Pages (from-to)2319–2324
Number of pages6
JournalBlood Advances
Volume5
Issue number9
DOIs
Publication statusPublished - 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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