Respective roles of Glycoprotein VI and FcγRIIA in the regulation of αIIbβ3‐mediated platelet activation to fibrinogen, thrombus buildup, and stability
Abstract Background The interplay between platelets and fibrinogen is the cornerstone of thrombus formation. Integrin αIIbβ3 is the main platelet adhesion receptor for fibrinogen and mediates an outside‐in signal upon ligand binding that reinforces platelet activation. In addition, FcγRIIA and glyco...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-07-01
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| Series: | Research and Practice in Thrombosis and Haemostasis |
| Online Access: | https://doi.org/10.1002/rth2.12551 |
| _version_ | 1797701877215789056 |
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| author | Muhammad Usman Ahmed Nicolas Receveur Emily Janus‐Bell Clarisse Mouriaux Christian Gachet Martine Jandrot‐Perrus Béatrice Hechler Elizabeth E. Gardiner Pierre H. Mangin |
| author_facet | Muhammad Usman Ahmed Nicolas Receveur Emily Janus‐Bell Clarisse Mouriaux Christian Gachet Martine Jandrot‐Perrus Béatrice Hechler Elizabeth E. Gardiner Pierre H. Mangin |
| author_sort | Muhammad Usman Ahmed |
| collection | DOAJ |
| description | Abstract Background The interplay between platelets and fibrinogen is the cornerstone of thrombus formation. Integrin αIIbβ3 is the main platelet adhesion receptor for fibrinogen and mediates an outside‐in signal upon ligand binding that reinforces platelet activation. In addition, FcγRIIA and glycoprotein VI (GPVI) contribute to platelet activation on fibrinogen, thereby participating in thrombus growth and stability. To date, the relative importance of these two immunoreceptor tyrosine‐based activation motif‐bearing receptors in these processes remains unknown. Objective The aim of this study was to evaluate the relative contributions of FcγRIIA and GPVI to platelet activation on fibrinogen and subsequent thrombus growth and stability. Methods We evaluated human and mouse platelet adhesion to fibrinogen in static assays and a flow‐based approach to evaluate the contribution of FcγRIIA and GPVI to thrombus growth and stability. Results We first confirmed that integrin αIIbβ3 is the key receptor supporting platelet adhesion and spreading on fibrinogen. Using human platelets treated with pharmacological blocking agents and transgenic mouse platelets expressing human receptors, data indicate that GPVI, but not FcγRIIA, plays a prominent role in platelet activation on fibrinogen. Moreover, using a flow‐based assay, we observed that blockade of GPVI with 1G5, but not FcγRIIA with IV.3, prevents thrombus growth. Finally, we observed that 1G5, but not IV.3, promotes the disaggregation of thrombi formed on collagen in vitro. Conclusion This study provides evidence that GPVI, but not FcγRIIA, induces platelet activation and spreading on fibrinogen, and promotes thrombus buildup and stability. |
| first_indexed | 2024-03-12T04:42:00Z |
| format | Article |
| id | doaj.art-79f281201ef34fe6b728f32d8e5e66e2 |
| institution | Directory Open Access Journal |
| issn | 2475-0379 |
| language | English |
| last_indexed | 2024-03-12T04:42:00Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Research and Practice in Thrombosis and Haemostasis |
| spelling | doaj.art-79f281201ef34fe6b728f32d8e5e66e22023-09-03T09:34:39ZengElsevierResearch and Practice in Thrombosis and Haemostasis2475-03792021-07-0155n/an/a10.1002/rth2.12551Respective roles of Glycoprotein VI and FcγRIIA in the regulation of αIIbβ3‐mediated platelet activation to fibrinogen, thrombus buildup, and stabilityMuhammad Usman Ahmed0Nicolas Receveur1Emily Janus‐Bell2Clarisse Mouriaux3Christian Gachet4Martine Jandrot‐Perrus5Béatrice Hechler6Elizabeth E. Gardiner7Pierre H. Mangin8Université de Strasbourg INSERM EFS Grand‐Est BPPS UMR‐S1255 FMTS Strasbourg FranceUniversité de Strasbourg INSERM EFS Grand‐Est BPPS UMR‐S1255 FMTS Strasbourg FranceUniversité de Strasbourg INSERM EFS Grand‐Est BPPS UMR‐S1255 FMTS Strasbourg FranceUniversité de Strasbourg INSERM EFS Grand‐Est BPPS UMR‐S1255 FMTS Strasbourg FranceUniversité de Strasbourg INSERM EFS Grand‐Est BPPS UMR‐S1255 FMTS Strasbourg FranceUniversité de Paris INSERM Hôpital Bichat UMR‐S1148 Paris FranceUniversité de Strasbourg INSERM EFS Grand‐Est BPPS UMR‐S1255 FMTS Strasbourg FranceDepartment of Cancer Biology and Therapeutics The John Curtin School of Medical Research Australian National University Canberra AustraliaUniversité de Strasbourg INSERM EFS Grand‐Est BPPS UMR‐S1255 FMTS Strasbourg FranceAbstract Background The interplay between platelets and fibrinogen is the cornerstone of thrombus formation. Integrin αIIbβ3 is the main platelet adhesion receptor for fibrinogen and mediates an outside‐in signal upon ligand binding that reinforces platelet activation. In addition, FcγRIIA and glycoprotein VI (GPVI) contribute to platelet activation on fibrinogen, thereby participating in thrombus growth and stability. To date, the relative importance of these two immunoreceptor tyrosine‐based activation motif‐bearing receptors in these processes remains unknown. Objective The aim of this study was to evaluate the relative contributions of FcγRIIA and GPVI to platelet activation on fibrinogen and subsequent thrombus growth and stability. Methods We evaluated human and mouse platelet adhesion to fibrinogen in static assays and a flow‐based approach to evaluate the contribution of FcγRIIA and GPVI to thrombus growth and stability. Results We first confirmed that integrin αIIbβ3 is the key receptor supporting platelet adhesion and spreading on fibrinogen. Using human platelets treated with pharmacological blocking agents and transgenic mouse platelets expressing human receptors, data indicate that GPVI, but not FcγRIIA, plays a prominent role in platelet activation on fibrinogen. Moreover, using a flow‐based assay, we observed that blockade of GPVI with 1G5, but not FcγRIIA with IV.3, prevents thrombus growth. Finally, we observed that 1G5, but not IV.3, promotes the disaggregation of thrombi formed on collagen in vitro. Conclusion This study provides evidence that GPVI, but not FcγRIIA, induces platelet activation and spreading on fibrinogen, and promotes thrombus buildup and stability.https://doi.org/10.1002/rth2.12551 |
| spellingShingle | Muhammad Usman Ahmed Nicolas Receveur Emily Janus‐Bell Clarisse Mouriaux Christian Gachet Martine Jandrot‐Perrus Béatrice Hechler Elizabeth E. Gardiner Pierre H. Mangin Respective roles of Glycoprotein VI and FcγRIIA in the regulation of αIIbβ3‐mediated platelet activation to fibrinogen, thrombus buildup, and stability Research and Practice in Thrombosis and Haemostasis |
| title | Respective roles of Glycoprotein VI and FcγRIIA in the regulation of αIIbβ3‐mediated platelet activation to fibrinogen, thrombus buildup, and stability |
| title_full | Respective roles of Glycoprotein VI and FcγRIIA in the regulation of αIIbβ3‐mediated platelet activation to fibrinogen, thrombus buildup, and stability |
| title_fullStr | Respective roles of Glycoprotein VI and FcγRIIA in the regulation of αIIbβ3‐mediated platelet activation to fibrinogen, thrombus buildup, and stability |
| title_full_unstemmed | Respective roles of Glycoprotein VI and FcγRIIA in the regulation of αIIbβ3‐mediated platelet activation to fibrinogen, thrombus buildup, and stability |
| title_short | Respective roles of Glycoprotein VI and FcγRIIA in the regulation of αIIbβ3‐mediated platelet activation to fibrinogen, thrombus buildup, and stability |
| title_sort | respective roles of glycoprotein vi and fcγriia in the regulation of αiibβ3 mediated platelet activation to fibrinogen thrombus buildup and stability |
| url | https://doi.org/10.1002/rth2.12551 |
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