Extracellular RNA induce neutrophil recruitment via endothelial TLR3 during venous thrombosis after vascular injury
Abstract Background Venous thromboembolism is associated with endothelial cell activation that contributes to the inflammation-dependent activation of the coagulation system. Cellular damages are associated with the release of different species of extracellular RNA (eRNA) involved in inflammation and coagulation. TLR3, which recognizes (viral) double-stranded RNA, single-stranded RNA, and also self-RNA fragments might be the receptor of these eRNA during venous thromboembolism. We investigate how eRNA regulate endothelial function through TLR3 and contribute to venous thromboembolism.Methods and Results Thrombus formation and size in WT and TLR3 deficient (-/-) mice were monitored by ultrasonography after venous thrombosis using the FeCl3and stasis models. Mice were treated with RNase1, poly(I:C) or RNA extracted from murine endothelial cells (eRNA). Gene expression and signaling pathway activation were analyzed in HEK293T cells overexpressing TLR3 in response to eRNA or in HUVECs transfected with a siRNA against TLR3. Plasma clot formation on treated HUVECs was analyzed. Thrombosis exacerbated RNA release in vivo and increased RNA content within the thrombus. RNase1 treatment reduced thrombus size compared to vehicle-treated mice. Poly(I:C) and eRNA treatments increased thrombus size in WT mice, but not in TLR3-/-mice, by bolstering neutrophil recruitment. Mechanistically, TLR3 activation in endothelial cells promotes CXCL5 secretion and neutrophil recruitment in vitro. eRNA triggered plasma clot formation. eRNA mediate these effects through TLR3-dependent activation of NFκB.Conclusions We show that eRNA and TLR3 activation enhance venous thromboembolism through neutrophil recruitment and secretion of CXCL5..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 27. Jan. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Najem, Maria Y. [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2024.01.18.576322 |
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| PPN (Katalog-ID): |
XBI042258561 |
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| 245 | 1 | 0 | |a Extracellular RNA induce neutrophil recruitment via endothelial TLR3 during venous thrombosis after vascular injury |
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| 520 | |a Abstract Background Venous thromboembolism is associated with endothelial cell activation that contributes to the inflammation-dependent activation of the coagulation system. Cellular damages are associated with the release of different species of extracellular RNA (eRNA) involved in inflammation and coagulation. TLR3, which recognizes (viral) double-stranded RNA, single-stranded RNA, and also self-RNA fragments might be the receptor of these eRNA during venous thromboembolism. We investigate how eRNA regulate endothelial function through TLR3 and contribute to venous thromboembolism.Methods and Results Thrombus formation and size in WT and TLR3 deficient (-/-) mice were monitored by ultrasonography after venous thrombosis using the FeCl3and stasis models. Mice were treated with RNase1, poly(I:C) or RNA extracted from murine endothelial cells (eRNA). Gene expression and signaling pathway activation were analyzed in HEK293T cells overexpressing TLR3 in response to eRNA or in HUVECs transfected with a siRNA against TLR3. Plasma clot formation on treated HUVECs was analyzed. Thrombosis exacerbated RNA release in vivo and increased RNA content within the thrombus. RNase1 treatment reduced thrombus size compared to vehicle-treated mice. Poly(I:C) and eRNA treatments increased thrombus size in WT mice, but not in TLR3-/-mice, by bolstering neutrophil recruitment. Mechanistically, TLR3 activation in endothelial cells promotes CXCL5 secretion and neutrophil recruitment in vitro. eRNA triggered plasma clot formation. eRNA mediate these effects through TLR3-dependent activation of NFκB.Conclusions We show that eRNA and TLR3 activation enhance venous thromboembolism through neutrophil recruitment and secretion of CXCL5. | ||
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| 700 | 1 | |a Laurance, Sandrine |4 aut | |
| 700 | 1 | |a Bertin, François-René |4 aut | |
| 700 | 1 | |a Gourdou-Latyszenok, Virginie |4 aut | |
| 700 | 1 | |a Gourhant, Lénaïck |4 aut | |
| 700 | 1 | |a Le Gall, Lauriane |4 aut | |
| 700 | 1 | |a Le Corre, Rozenn |4 aut | |
| 700 | 1 | |a Couturaud, Francis |4 aut | |
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