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J Clin Invest. 2019 Apr 16;130. pii: 124804. doi: 10.1172/JCI124804.

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

Author information

1
Division of Cardiovascular Medicine, Frankel Cardiovascular Center.
2
Department of Pharmacology.
3
Division of Rheumatology, and.
4
Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.
5
Department of Chemical Engineering, University of Michigan College of Engineering, Ann Arbor, Michigan, USA.
6
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
7
Section of Cardiology, Ann Arbor Veterans Health System, Ann Arbor, Michigan, USA.

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.

KEYWORDS:

Cardiovascular disease; Inflammation; Innate immunity; Thrombosis; Vascular Biology

PMID:
30990798
DOI:
10.1172/JCI124804
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