Crosstalk between coagulation and innate immunity contributes to the progression of many diseases, including infection and cardiovascular disease. Venous thromboembolism (VTE), including pulmonary embolism and deep vein thrombosis (DVT), is among the most common causes of cardiovascular death. Here, we show that inflammasome activation and subsequent pyroptosis play an important role in the development of venous thrombosis. Using a flow restriction induced mouse venous thrombosis model in the inferior vena cava (IVC), we show that deficiency of caspase-1, but not caspase-11, protected against flow restriction induced thrombosis. Interleukin-1b expression increased in the IVC following ligation, indicating that inflammasome is activated during injury. Deficiency of gasdermin D (GSDMD), an essential mediator of pyroptosis, protected against restriction-induced venous thrombosis. After induction of venous thrombosis, fibrin was deposited in the veins of wild-Type mice, as detected using immunoblotting with a monoclonal antibody that specifically recognizes mouse fibrin, but not in the caspase-1 deficient or GSDMD-deficient mice. Depletion of macrophages by gadolinium chloride or deficiency of tissue factor also protected against venous thrombosis. Our data reveal that tissue factor released from pyroptotic monocytes and macrophages following inflammasome activation triggers thrombosis.
|Number of pages||5|
|State||Published - Jun 22 2021|
Bibliographical noteFunding Information:
This work was supported by grants K99HL145117 (C.W., who is a K99 awardee); National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI) grant R01 HL124266 (A.A.-L.); National Science Foundation grant CHE-1709381 (Y.W.), NIH/National Institute of Allergy and Infectious Diseases grants R56 AI137020 (Y.W.), R21 AI142063 (Y.W.), NIH/NHLBI grant R01 HL142640 (Y.W.), NIH/National Institute of General Medical Sciences (NIGMS) grants R01 GM132443 (Y.W.); and NIH/NHLBI R01 HL146744 (Z.L.), R01 HL142640 (Z.L.), and NIH/NIGMS R01 GM132443 (Z.L.).
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