Abstract Number: OC 05.3
Meeting: ISTH 2020 Congress
Background: Deep vein thrombosis (DVT) is a debilitating and sometimes life-threatening disease that results from platelet and leukocyte accumulation at the vessel wall in a process known as thromboinflammation. Activated neutrophils release neutrophil extracellular traps (NETs) composed of DNA and histones, and destruction of NETs by DNase, or prevention of their formation, protects mice from DVT. Inflammasomes are molecular complexes, which set an inflammatory cascade in motion by activating caspase-1, leading to IL-1β activation.
Aims: In this project, we aimed to investigate the bidirectional interactions between inflammasomes and NETs in the context of murine DVT.
Methods: DVT was induced in C57BL/6 male mice by partial ligation of the inferior vena cava (IVC). Thrombus formation was evaluated at 48 hours post-surgery.
Results: Following IVC stenosis, we detected active caspase-1 in approximately 50% of platelets located within thrombi, and 10% of platelets in the circulation. Leukocytes containing active caspase-1 were restricted to the thrombus. Intravital imaging revealed the presence of both NETs and active caspase-1 signal in the IVC post stenosis. Histones and neutrophils undergoing NETosis induced caspase-1 activation and aggregation in washed human platelets. Image analysis of cells stimulated in vitro showed that most inflammasome-containing cells were localized within NETs, whereas NETosis occurred in the absence of inflammasomes. This implies that NETs likely serve as a basis for and a primary inducer of inflammasomes rather than vice versa. In thrombi, NETs and inflammasomes were colocalized. Inhibition of caspase-1 by a specific inhibitor Ac-YVAD-cmk reduced thrombosis incidence and NETosis in thrombi.
Conclusions: Collectively, we show that NET formation and inflammasome assembly are interconnected events in DVT. We suggest that these form an inflammatory circuit, resulting in IL-1β activation, which creates a positive feedback loop promoting further activation of platelets and endothelial cells. Our work provides a rationale for targeting this circuit for prevention of venous thrombosis.
To cite this abstract in AMA style:Campos J, Ponomaryov T, De Prendegast A, Brill A. Neutrophil Extracellular Traps and Inflammasomes Form an Inflammatory Circuit Promoting Venous Thrombosis [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/neutrophil-extracellular-traps-and-inflammasomes-form-an-inflammatory-circuit-promoting-venous-thrombosis/. Accessed May 6, 2021.
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