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NLRP3 regulates platelet integrin αIIbβ3 outside-in signaling, hemostasis and arterial thrombosis
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 in vitro. However, th...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ferrata Storti Foundation
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119128/ https://www.ncbi.nlm.nih.gov/pubmed/29794149 http://dx.doi.org/10.3324/haematol.2018.191700 |
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author | 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 |
author_facet | 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 |
author_sort | Qiao, Jianlin |
collection | PubMed |
description | 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 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 αIIbβ3 signaling transduction. Using NLRP3(−/−) mice, we showed that NLRP3-deficient platelets do not have significant differences in expression of the platelet-specific adhesive receptors αIIbβ3 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 PLCγ2 in response to thrombin stimulation. Interestingly, addition of exogenous recombinant interleukin-1β reversed the defect in NLRP3(−/−) platelet spreading and clot retraction, and restored thrombin-induced phosphorylation of c-Src/Syk/PLCγ2, whereas an anti-interleukin-1β 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 αIIbβ3 outside-in signaling. This study identifies a novel role for NLRP3 and interleukin-1β in platelet function, and provides a new potential link between thrombosis and inflammation, suggesting that therapies targeting NLRP3 or interleukin-1β might be beneficial for treating inflammation-associated thrombosis. |
format | Online Article Text |
id | pubmed-6119128 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Ferrata Storti Foundation |
record_format | MEDLINE/PubMed |
spelling | pubmed-61191282018-09-10 NLRP3 regulates platelet integrin αIIbβ3 outside-in signaling, hemostasis and arterial thrombosis 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 Haematologica Article 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 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 αIIbβ3 signaling transduction. Using NLRP3(−/−) mice, we showed that NLRP3-deficient platelets do not have significant differences in expression of the platelet-specific adhesive receptors αIIbβ3 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 PLCγ2 in response to thrombin stimulation. Interestingly, addition of exogenous recombinant interleukin-1β reversed the defect in NLRP3(−/−) platelet spreading and clot retraction, and restored thrombin-induced phosphorylation of c-Src/Syk/PLCγ2, whereas an anti-interleukin-1β 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 αIIbβ3 outside-in signaling. This study identifies a novel role for NLRP3 and interleukin-1β in platelet function, and provides a new potential link between thrombosis and inflammation, suggesting that therapies targeting NLRP3 or interleukin-1β might be beneficial for treating inflammation-associated thrombosis. Ferrata Storti Foundation 2018-09 /pmc/articles/PMC6119128/ /pubmed/29794149 http://dx.doi.org/10.3324/haematol.2018.191700 Text en Copyright© 2018 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher. |
spellingShingle | Article 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 NLRP3 regulates platelet integrin αIIbβ3 outside-in signaling, hemostasis and arterial thrombosis |
title | NLRP3 regulates platelet integrin αIIbβ3 outside-in signaling, hemostasis and arterial thrombosis |
title_full | NLRP3 regulates platelet integrin αIIbβ3 outside-in signaling, hemostasis and arterial thrombosis |
title_fullStr | NLRP3 regulates platelet integrin αIIbβ3 outside-in signaling, hemostasis and arterial thrombosis |
title_full_unstemmed | NLRP3 regulates platelet integrin αIIbβ3 outside-in signaling, hemostasis and arterial thrombosis |
title_short | NLRP3 regulates platelet integrin αIIbβ3 outside-in signaling, hemostasis and arterial thrombosis |
title_sort | nlrp3 regulates platelet integrin αiibβ3 outside-in signaling, hemostasis and arterial thrombosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119128/ https://www.ncbi.nlm.nih.gov/pubmed/29794149 http://dx.doi.org/10.3324/haematol.2018.191700 |
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