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Ectonucleotidase tri(di)phosphohydrolase-1 (ENTPD-1) disrupts inflammasome/interleukin 1β-driven venous thrombosis
Vinita Yadav1, Liguo Chi1, Raymond Zhao1
1Division of Cardiovascular Medicine, Frankel Cardiovascular Center.
Insights
The enzyme CD39 (ectonucleoside tri(di)phosphohydrolase) normally prevents deep vein thrombosis (DVT) by reducing inflammation and coagulation. CD39 deficiency significantly increases DVT risk by promoting inflammatory pathways.
Area of Science:
- Cardiovascular Biology
- Immunology
- Thrombosis Research
Background:
- Deep vein thrombosis (DVT) is a major cause of cardiovascular mortality, yet its molecular drivers remain incompletely understood.
- DVT pathogenesis involves complex interactions between coagulation and inflammation.
- Ectonucleoside tri(di)phosphohydrolase (ENTPD1, CD39) is a cell surface enzyme that hydrolyzes nucleotides, mitigating inflammation and thrombosis.
Purpose of the Study:
- To investigate the role of CD39 in regulating venous thrombosis.
- To elucidate the molecular mechanisms by which CD39 influences thrombo-inflammation.
Main Methods:
- Utilized a murine model of inferior vena cava stenosis to induce deep vein thrombosis.
- Assessed thrombosis severity, leukocyte recruitment, and inflammatory markers in CD39-deficient and wild-type mice.
- Analyzed signaling pathways including NFκB phosphorylation, inflammasome activation, and IL-1β release.
Main Results:
- CD39 deficiency led to a >2-fold increase in venous thrombogenesis.
- Absence of CD39 resulted in heightened leukocyte engagement, neutrophil extracellular trap formation, fibrin deposition, and tissue factor activation.
- CD39-deficient mice exhibited increased NFκB phosphorylation, NLRP3 inflammasome activation, and IL-1β release.
- Neutralization of IL-1β significantly attenuated thrombosis in CD39-deficient mice.
Conclusions:
- CD39 acts as a critical vascular checkpoint, inhibiting venous thrombosis by suppressing the crosstalk between inflammation and coagulation.
- Interleukin-1β (IL-1β) is identified as a key mediator accelerating venous thrombo-inflammation.
- Targeting CD39 or IL-1β may offer therapeutic strategies for preventing DVT.
Abstract:
Deep vein thrombosis (DVT), caused by alterations in venous homeostasis is the third most common cause of cardiovascular mortality; however, key molecular determinants in venous thrombosis have not been fully elucidated. Several lines of evidence indicate that DVT occurs at the intersection of dysregulated inflammation and coagulation. The enzyme ectonucleoside tri(di)phosphohydrolase (ENTPD1, also known as CD39) is a vascular ecto-apyrase on the surface of leukocytes and the endothelium that inhibits intravascular inflammation and thrombosis by hydrolysis of phosphodiester bonds from nucleotides released by activated cells. Here, we evaluated the contribution of CD39 to venous thrombosis in a restricted-flow model of murine inferior vena cava stenosis. CD39-deficiency conferred a >2-fold increase in venous thrombogenesis, characterized by increased leukocyte engagement, neutrophil extracellular trap formation, fibrin, and local activation of tissue factor in the thrombotic milieu. This was orchestrated by increased phosphorylation of the p65 subunit of NFκB, activation of the NLRP3 inflammasome, and interleukin-1β (IL-1β) release in CD39-deficient mice. Substantiating these findings, an IL-1β-neutralizing antibody attenuated the thrombosis risk in CD39-deficient mice. These data demonstrate that IL-1β is a key accelerant of venous thrombo-inflammation, which can be suppressed by CD39. CD39 inhibits in vivo crosstalk between inflammation and coagulation pathways, and is a critical vascular checkpoint in venous thrombosis.
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