Neutrophil extracellular traps and inflammasomes cooperatively promote venous thrombosis in mice

被引:55
作者
Campos, Joana [1 ]
Ponomaryov, Tatyana [1 ,4 ]
De Prendergast, Alexandra [1 ,5 ]
Whitworth, Katharine [1 ]
Smith, Christopher W. [1 ]
Khan, Abdullah O. [1 ]
Kavanagh, Dean [1 ]
Brill, Alexander [1 ,2 ,3 ]
机构
[1] Univ Birmingham, Coll Med & Dent Sci, Inst Cardiovasc Sci, Birmingham B15 2TT, W Midlands, England
[2] Univ Birmingham, Ctr Membrane Prot & Receptors COMPARE, Birmingham, W Midlands, England
[3] Univ Nottingham, Ctr Membrane Prot & Receptors COMPARE, Nottingham, England
[4] Plasticell Ltd, Stevenage, Herts, England
[5] Northern Lincolnshire & Goole NHS Fdn Trust, Diana Princess Wales Hosp, Grimsby, England
基金
英国惠康基金;
关键词
DEEP-VEIN THROMBOSIS; NLRP3; INFLAMMASOME; ACTIVATION;
D O I
10.1182/bloodadvances.2020003377
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:2319 / 2324
页数:6
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