Zhang Jie, Zhu Hui, Dai Yue, Jiang Huimin, Li Yingying, Chen Shuang, Sun Yueyue, Xu Mengdi, Nechipurenko Dmitry Yu, Li Zhenyu, Zeng Lingyu, Panteleev Mikhail A, Xu Kailin, Qiao Jianlin
Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
Faculty of Physics, Lomonosov Moscow State University, Moscow, Russia; Center for Theoretical Problems of Physico-chemical Pharmacology, Russian Academy of Science, Moscow, Russia; Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
J Thromb Haemost. 2025 Sep;23(9):2890-2902. doi: 10.1016/j.jtha.2025.05.031. Epub 2025 Jun 6.
Inflammation-induced injury of venous endothelium is the first trigger of deep vein thrombosis (DVT). We previously showed NLRP3 regulates platelet function and arterial thrombosis. However, whether platelet NLRP3 involves in venous thrombosis remains unclear.
In this study, we intended to investigate the role of NLRP3 in venous thrombosis by using NLRP3 knockout mice and platelet-specific NLRP3 knockout mice.
DVT model was established through ligation of the inferior vena cava. After 48 hours of ligation, inferior vena cava sample was excised to measure thrombi length and weight, the recruitment of platelets, neutrophils, monocytes, and neutrophil extracellular trap (NET) formation by immunofluorescence staining.
Deficiency of NLRP3 reduced the incidence and severity of venous thrombosis, inhibited the recruitment and accumulation of platelets, neutrophils, and monocytes in venous thrombi, and reduced NET formation as well as interleukin (IL)-1β and IL-18 release. Additionally, platelet NLRP3 is the major source of elevated IL-1β in the venous thrombi, and adoptive transfer of platelets to NLRP3 mice increased IL-1β level in thrombi and promoted venous thrombosis and NET formation. Moreover, platelet NLRP3 deficiency inhibited NET formation induced by activated platelets in vitro.
Our study demonstrated that deficiency of NLRP3 reduces the incidence and the severity of venous thrombosis with platelet NLRP3 playing a predominant role, indicating that NLRP3 might be a therapeutic target for the treatment of venous thrombosis.
炎症诱导的静脉内皮损伤是深静脉血栓形成（DVT）的首要触发因素。我们之前表明NLRP3调节血小板功能和动脉血栓形成。然而，血小板NLRP3是否参与静脉血栓形成仍不清楚。
在本研究中，我们旨在通过使用NLRP3基因敲除小鼠和血小板特异性NLRP3基因敲除小鼠来研究NLRP3在静脉血栓形成中的作用。
通过结扎下腔静脉建立DVT模型。结扎48小时后，切除下腔静脉样本以测量血栓长度和重量，通过免疫荧光染色检测血小板、中性粒细胞、单核细胞的募集以及中性粒细胞胞外陷阱（NET）的形成。
NLRP3缺乏降低了静脉血栓形成的发生率和严重程度，抑制了血小板、中性粒细胞和单核细胞在静脉血栓中的募集和聚集，并减少了NET形成以及白细胞介素（IL）-1β和IL-18的释放。此外，血小板NLRP3是静脉血栓中IL-1β升高的主要来源，将血小板过继转移至NLRP3基因敲除小鼠可增加血栓中IL-1β水平并促进静脉血栓形成和NET形成。而且，血小板NLRP3缺乏抑制了体外活化血小板诱导的NET形成。
我们的研究表明，NLRP3缺乏降低了静脉血栓形成的发生率和严重程度，其中血小板NLRP3起主要作用，这表明NLRP3可能是治疗静脉血栓形成的一个治疗靶点。
