Toll-like receptor 9 signaling is critical for early experimental deep vein thrombosis resolution.
Toll-like receptor 9 signaling is critical for early experimental deep vein thrombosis resolution.
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DOI：
10.1161/atvbaha.110.216317
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发表时间：
2011-01
期刊：
影响因子：
--
通讯作者：
Kunkel SL
中科院分区：
文献类型：
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作者：
Henke PK;Mitsuya M;Luke CE;Elfline MA;Baldwin JF;Deatrick KB;Diaz JA;Sood V;Upchurch GR;Wakefield TW;Hogaboam C;Kunkel SL
Toll 样受体 (TLR) 连接先天免疫和宿主反应，包括炎症。静脉血栓 (VT) 等无菌性炎症可能涉及 TLR 信号传导，包括 TLR9。使用停滞性 VT 小鼠模型研究了 TLR9 信号传导对血栓溶解的影响。与 WT 相比，TLR9 -/− 小鼠在第 2 天和第 8 天的 VT 明显更大，尽管第 2 天的血栓 PMN 增加了 2 倍，第 8 天的单核细胞增加了 2 倍，而第 8 天的血栓胶原和新血管形成分别减少了 55% 和 37%。巧合的是，在 TLR9 -/− 小鼠血栓中观察到纤维蛋白原减少和凝血酶-抗凝血酶复合物增加。与 WT 相比，TLR9 -/− 小鼠的静脉壁 IFNα、IL1α 和 IL2 显着减少。血栓细胞死亡途径标记物在第 2 天时没有显着改变，但在第 8 天时 TLR9 −/− 血栓中 caspase 1 减少。 MyD88 赋予 TLR9 细胞内信号传导，但 MyD88−/− 小鼠具有与 WT 相似的 VT 分辨率。然而，NOTCH 配体 delta-like 4 的抑制与较大的 VT 相关。最后，TLR9 激动剂刺激与较小的 VT 相关。 TLR9 信号传导通过调节无菌炎症、维持 TH1 环境以及影响血栓形成途径，对于早期和中期 VT 缓解至关重要。
Toll like receptors (TLR) bridge innate immunity and host responses, including inflammation. Sterile inflammation such as a venous thrombus (VT) may involve TLR signaling, including TLR9. TLR9 signaling on thrombus resolution was investigated using a mouse model of stasis VT. VT were significantly larger in TLR9 −/− mice as compared with WT at 2 and 8 days, despite a 2 fold increase in thrombus PMN at 2d, and monocytes at 8d, while thrombus collagen and neovascularization was 55% and 37% less at 8d. Coincidently, decreased fibrinogen and increased thrombin-antithrombin complex were observed in TLR9 −/− mice thrombi. Vein wall IFNα, IL1α, and IL2 was significantly reduced in TLR9 −/− mice as compared to WT. Thrombus cell death pathway markers were not significantly altered at 2d, but caspase 1 was reduced in TLR9 −/− thrombi at 8d. MyD88 confers TLR9 intracellular signaling, but MyD88−/− mice had similar VT resolution as WT. However, inhibition of the NOTCH ligand delta-like 4 was associated with larger VT. Finally, stimulation with a TLR9 agonist was associated with smaller VT. TLR9 signaling is integral for early and mid VT resolution through modulation of sterile inflammation, maintaining a TH1 milieu, and effects on the thrombosis pathway.