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NLRP3 regulates platelet integrin ?IIb?3 outside-in signaling, hemostasis and arterial thrombosis.

ABSTRACT: 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? 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 ?IIb?3 signaling transduction. Using NLRP3-/- mice, we showed that NLRP3-deficient platelets do not have significant differences in expression of the platelet-specific adhesive receptors ?IIb?3 integrin, GPIba or GPVI; however, NLRP3-/- 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 clot retraction, concomitant with decreased phosphorylation of c-Src, Syk and PLC?2 in response to thrombin stimulation. Interestingly, addition of exogenous recombinant interleukin-1? reversed the defect in NLRP3-/- platelet spreading and clot retraction, and restored thrombin-induced phosphorylation of c-Src/Syk/PLC?2, whereas an anti-interleukin-1? 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 ?IIb?3 outside-in signaling. This study identifies a novel role for NLRP3 and interleukin-1? in platelet function, and provides a new potential link between thrombosis and inflammation, suggesting that therapies targeting NLRP3 or interleukin-1? might be beneficial for treating inflammation-associated thrombosis.

SUBMITTER: Qiao J

PROVIDER: S-EPMC6119128 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Qiao Jianlin J Wu Xiaoqing X Luo Qi Q Wei Guangyu G Xu Mengdi M Wu Yulu Y Liu Yun Y Li Xiaoqian X Zi Jie J Ju Wen W Fu Lin L Chen Chong C Wu Qingyun Q Zhu Shengyun S Qi Kunming K Li Depeng D Li Zhenyu Z Andrews Robert K RK Zeng Lingyu L Gardiner Elizabeth E EE Xu Kailin K

Haematologica 20180524 9

In addition to their hemostatic function, platelets play an important role in regulating the inflammatory response. The platelet NLRP3 inflammasome not only promotes interleukin-1β secretion, but was also found to be upregulated during platelet activation and thrombus formation <i>in vitro</i> However, the role of NLRP3 in platelet function and thrombus formation <i>in vivo</i> remains unclear. In this study, we aimed to investigate the role of NLRP3 in platelet integrin αIIbβ3 signaling transdu ...[more]

PMID: 29794149

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Dataset Information

NLRP3 regulates platelet integrin ?IIb?3 outside-in signaling, hemostasis and arterial thrombosis.

Publications

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

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