Neutrophil Extracellular Traps and Inflammasomes Form an Inflammatory Circuit Promoting Venous Thrombosis

On Sunday, Joana Campos of the Institute of Cardiovascular Sciences, College of Medical and Dental Sciences at the University of Birmingham, United Kingdom, presented results from research that looked into the bidirectional interactions between inflammasomes and neutrophil extracellular traps (NETs) in the context of murine deep venous thrombosis (DVT). Activated neutrophils release 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 that set an inflammatory cascade in motion by activating caspase-1, leading to IL-1β activation.

Campos commented that 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. Post IVC stenosis, active caspase-1 was detected 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. 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, suggesting that NETs likely serve as a basis for and a primary inducer of inflammasomes rather than vice versa. In thrombi, NETs and inflammasomes were co-localized. Inhibition of caspase-1 by a specific inhibitor, Ac-YVAD-cmk, reduced thrombosis incidence and NETosis in thrombi.

Campos concluded that their work provided a rationale for targeting this circuit for prevention of venous thrombosis, as NET formation and inflammasome assembly associated with one another in DVT. These events form an inflammatory circuit, resulting in IL-1β activation, creating a positive feedback loop that promotes further activation of platelets and endothelial cells.

Read the full abstract here.
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