NLRP3 regulates platelet integrin αIIbβ3 outside-in signaling, hemostasis and arterial thrombosis

作者：Qiao, Jianlin^*; Wu, Xiaoqing; Luo, Qi; Wei, Guangyu; Xu, Mengdi; Wu, Yulu; Liu, Yun; Li, Xiaoqian; Zi, Jie; Ju, Wen; Fu, Lin; Chen, Chong; Wu, Qingyun; Zhu, Shengyun; Qi, Kunming; Li, Depeng; Li, Zhenyu; Andrews, Robert K.; Zeng, Lingyu; Gardiner, Elizabeth E.; Xu, Kailin

来源：Haematologica-The Hematology Journal, 2018, 103(9): 1568-1576.

DOI：10.3324/haematol.2018.191700

• IMMUNE FUNCTIONS
• TYROSINE KINASE
• ACTIVATION
• INFLAMMATION
• IDENTIFICATION
• RETRACTION
• RECEPTORS
• PROTEINS
• ADHESION
• HUMANS

In addition to their hemostatic function, platelets play an important role in regulating the inflammatory response. The platelet NLRP3 inflammasome not only promotes interleukin-1 beta secretion, but was also found to be upregulated during platelet activation and thrombus formation in vitro. However, the role of NLRP3 in platelet function and thrombus formation in vivo remains unclear. In this study, we aimed to investigate the role of NLRP3 in platelet integrin alpha IIb beta 3 signaling transduction. Using NLIZP3(-/-) mice, we showed that NLRP3-deficient platelets do not have significant differences in expression of the platelet-specific adhesive receptors alpha IIb beta 3 integrin, GPIb alpha or GPVI; however, NLIZP3(-/-) platelets transfused into wild-type mice resulted in prolonged tail-bleeding time and delayed arterial thrombus formation, as well as exhibiting impaired spreading on immobilized fibrinogen and defective dot retraction, concomitant with decreased phosphorylation of c-Src, Syk and PLC gamma 2 in response to thrombin stimulation. Interestingly, addition of exogenous recombinant interleukin-1 beta reversed the defect in NLIZP3(-/- )platelet spreading and dot retraction, and restored thrombin-induced phosphorylation of c-Src/Syk/PLC gamma 2, whereas an anti-interleukin-1 beta antibody blocked spreading and clot retraction mediated by wild-type platelets. Using the direct NLRP3 inhibitor, CY-09, we demonstrated significantly reduced human platelet aggregation in response to threshold concentrations of collagen and ADP, as well as impaired clot retraction in CY-09-treated human platelets, supporting a role for NLRP3 also in regulating human platelet alpha IIb beta 3 outside-in signaling. This study identifies a novel role for NLRP3 and interleukin-1 beta in platelet function, and provides a new potential link between thrombosis and inflammation, suggesting that therapies targeting NLRP3 or interleukin-1 beta might be beneficial for treating inflammation-associated thrombosis.

• 出版日期2018-8-31
• 单位徐州医科大学