TY - JOUR
T1 - Inflammasome activation promotes venous thrombosis through pyroptosis
AU - Zhang, Yan
AU - Cui, Jian
AU - Zhang, Guoying
AU - Wu, Congqing
AU - Abdel-Latif, Ahmed
AU - Smyth, Susan S.
AU - Shiroishi, Toshihiko
AU - Mackman, Nigel
AU - Wei, Yinan
AU - Tao, Min
AU - Li, Zhenyu
N1 - Publisher Copyright:
© 2021 American Society of Hematology. All rights reserved.
PY - 2021/6/22
Y1 - 2021/6/22
N2 - 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.
AB - 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.
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U2 - 10.1182/bloodadvances.2020003041
DO - 10.1182/bloodadvances.2020003041
M3 - Article
C2 - 34152402
AN - SCOPUS:85108694675
SN - 2473-9529
VL - 5
SP - 2619
EP - 2623
JO - Blood advances
JF - Blood advances
IS - 12
ER -