ENTPD-1 disrupts inflammasome IL-1[beta]-driven venous thrombosis

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 dysr...

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Bibliographic Details
Published in:The Journal of clinical investigation 2019-07, Vol.129 (7), p.2872
Main Authors: Yadav, Vinita, Chi, Liguo, Zhao, Raymond, Tourdot, Benjamin E, Yalavarthi, Srilakshmi, Jacobs, Benjamin N, Banka, Alison, Liao, Hui, Koonse, Sharon, Anyanwu, Anuli C, Visovatti, Scott H, Holinstat, Michael A, Kahlenberg, J. Michelle, Knight, Jason S, Pinsky, David J, Kanthi, Yogendra
Format: Article
Language:English
Subjects:
Anakinra
Analysis
Antibodies
Bonds (Securities)
Endothelium
Enzymes
Fibrin
Health aspects
Homeostasis
Hydrolysis
Inflammation
Nucleotides
Stenosis
Thrombophlebitis
Thrombosis
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Summary: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 greater than 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 venous thrombogenesis was orchestrated by increased phosphorylation of the p65 subunit of NF-[kappa]B, activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, and IL-1[beta] release in CD39-deficient mice. Substantiating these findings, an IL-1[beta]-neutralizing antibody or the IL-1 receptor inhibitor anakinra attenuated the thrombosis risk in CD39- deficient mice. These data demonstrate that IL-1[beta] 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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI124804