IFITM3 regulates fibrinogen endocytosis and platelet reactivity in nonviral sepsis
Platelets and megakaryocytes are critical players in immune responses. Recent reports suggest infection and inflammation alter the megakaryocyte and platelet transcriptome to induce altered platelet reactivity. We determined whether nonviral sepsis induces differential platelet gene expression and reactivity. Nonviral sepsis upregulated IFN-induced transmembrane protein 3 (IFITM3), an IFN-responsive gene that restricts viral replication. As IFITM3 has been linked to clathrin-mediated endocytosis, we determined whether IFITM3 promoted endocytosis of α-granule proteins. IFN stimulation enhanced fibrinogen endocytosis in megakaryocytes and platelets from Ifitm+/+ mice, but not Ifitm-/- mice. IFITM3 overexpression or deletion in megakaryocytes demonstrated IFITM3 was necessary and sufficient to regulate fibrinogen endocytosis. Mechanistically, IFITM3 interacted with clathrin and αIIb and altered their plasma membrane localization into lipid rafts. In vivo IFN administration increased fibrinogen endocytosis, platelet reactivity, and thrombosis in an IFITM-dependent manner. In contrast, Ifitm-/- mice were completely rescued from IFN-induced platelet hyperreactivity and thrombosis. During murine sepsis, platelets from Ifitm+/+ mice demonstrated increased fibrinogen content and platelet reactivity, which was dependent on IFN-α and IFITMs. Platelets from patients with nonviral sepsis had increases in platelet IFITM3 expression, fibrinogen content, and hyperreactivity. These data identify IFITM3 as a regulator of platelet endocytosis, hyperreactivity, and thrombosis during inflammatory stress.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:132 |
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| Enthalten in: |
The Journal of clinical investigation - 132(2022), 23 vom: 01. Dez. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Campbell, Robert A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 05.12.2022 Date Revised 30.10.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/JCI153014 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM347099262 |
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| 100 | 1 | |a Campbell, Robert A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a IFITM3 regulates fibrinogen endocytosis and platelet reactivity in nonviral sepsis |
| 264 | 1 | |c 2022 | |
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| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 05.12.2022 | ||
| 500 | |a Date Revised 30.10.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Platelets and megakaryocytes are critical players in immune responses. Recent reports suggest infection and inflammation alter the megakaryocyte and platelet transcriptome to induce altered platelet reactivity. We determined whether nonviral sepsis induces differential platelet gene expression and reactivity. Nonviral sepsis upregulated IFN-induced transmembrane protein 3 (IFITM3), an IFN-responsive gene that restricts viral replication. As IFITM3 has been linked to clathrin-mediated endocytosis, we determined whether IFITM3 promoted endocytosis of α-granule proteins. IFN stimulation enhanced fibrinogen endocytosis in megakaryocytes and platelets from Ifitm+/+ mice, but not Ifitm-/- mice. IFITM3 overexpression or deletion in megakaryocytes demonstrated IFITM3 was necessary and sufficient to regulate fibrinogen endocytosis. Mechanistically, IFITM3 interacted with clathrin and αIIb and altered their plasma membrane localization into lipid rafts. In vivo IFN administration increased fibrinogen endocytosis, platelet reactivity, and thrombosis in an IFITM-dependent manner. In contrast, Ifitm-/- mice were completely rescued from IFN-induced platelet hyperreactivity and thrombosis. During murine sepsis, platelets from Ifitm+/+ mice demonstrated increased fibrinogen content and platelet reactivity, which was dependent on IFN-α and IFITMs. Platelets from patients with nonviral sepsis had increases in platelet IFITM3 expression, fibrinogen content, and hyperreactivity. These data identify IFITM3 as a regulator of platelet endocytosis, hyperreactivity, and thrombosis during inflammatory stress | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Bacterial infections | |
| 650 | 4 | |a Hematology | |
| 650 | 4 | |a Inflammation | |
| 650 | 4 | |a Platelets | |
| 650 | 4 | |a Thrombosis | |
| 650 | 7 | |a Clathrin |2 NLM | |
| 650 | 7 | |a Fibrinogen |2 NLM | |
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| 700 | 1 | |a Manne, Bhanu Kanth |e verfasserin |4 aut | |
| 700 | 1 | |a Banerjee, Meenakshi |e verfasserin |4 aut | |
| 700 | 1 | |a Middleton, Elizabeth A |e verfasserin |4 aut | |
| 700 | 1 | |a Ajanel, Abigail |e verfasserin |4 aut | |
| 700 | 1 | |a Schwertz, Hansjorg |e verfasserin |4 aut | |
| 700 | 1 | |a Denorme, Frederik |e verfasserin |4 aut | |
| 700 | 1 | |a Stubben, Chris |e verfasserin |4 aut | |
| 700 | 1 | |a Montenont, Emilie |e verfasserin |4 aut | |
| 700 | 1 | |a Saperstein, Samantha |e verfasserin |4 aut | |
| 700 | 1 | |a Page, Lauren |e verfasserin |4 aut | |
| 700 | 1 | |a Tolley, Neal D |e verfasserin |4 aut | |
| 700 | 1 | |a Lim, Diana L |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Samuel M |e verfasserin |4 aut | |
| 700 | 1 | |a Grissom, Colin K |e verfasserin |4 aut | |
| 700 | 1 | |a Sborov, Douglas W |e verfasserin |4 aut | |
| 700 | 1 | |a Krishnan, Anandi |e verfasserin |4 aut | |
| 700 | 1 | |a Rondina, Matthew T |e verfasserin |4 aut | |
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