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Ectonucleotidase tri(di)phosphohydrolase-1 (ENTPD-1) disrupts inflammasome/interleukin 1?-driven venous thrombosis.

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 NF?B, activation of the NLRP3 inflammasome, and interleukin-1? (IL-1?) release in CD39-deficient mice. Substantiating these findings, an IL-1?-neutralizing antibody attenuated the thrombosis risk in CD39-deficient mice. These data demonstrate that IL-1? 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.

SUBMITTER: Yadav V

PROVIDER: S-EPMC6597243 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Ectonucleotidase tri(di)phosphohydrolase-1 (ENTPD-1) disrupts inflammasome/interleukin 1β-driven venous thrombosis.

Yadav Vinita V Chi Liguo L Zhao Raymond R Tourdot Benjamin E BE Yalavarthi Srilakshmi S Jacobs Benjamin N BN Banka Alison A Liao Hui H Koonse Sharon S Anyanwu Anuli C AC Visovatti Scott H SH Holinstat Michael A MA Kahlenberg J Michelle JM Knight Jason S JS Pinsky David J DJ Kanthi Yogendra Y

The Journal of clinical investigation 20190416 7

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 in ...[more]

PMID: 30990798

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Dataset Information

Ectonucleotidase tri(di)phosphohydrolase-1 (ENTPD-1) disrupts inflammasome/interleukin 1?-driven venous thrombosis.

Publications

Ectonucleotidase tri(di)phosphohydrolase-1 (ENTPD-1) disrupts inflammasome/interleukin 1β-driven venous thrombosis.

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