Innate immune TLR7 signaling mediates platelet activation and platelet-leukocyte aggregate formation in murine bacterial sepsis.
Innate immune TLR7 signaling mediates platelet activation and platelet-leukocyte aggregate formation in murine bacterial sepsis.
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DOI：
10.1080/09537104.2022.2107627
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发表时间：
2022-11-17
期刊：
影响因子：
3.3
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中科院分区：
文献类型：
--
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血小板减少症是脓毒症的常见并发症，与较高的死亡率相关。活化的血小板表达CD 62 P，其促进血小板-白细胞聚集体（PLA）形成并促成脓毒症中的血小板减少症。我们已经报道了小鼠败血症中的血小板减少症部分归因于TLR 7信号传导，但其潜在机制尚不清楚。在目前的研究中，我们测试的假设，TLR 7介导的血小板活化和PLA的形成在败血症。在体外，与对照组（含0.05%DMSO的PBS）或经洛索立宾处理的TLR 7 −/−全血相比，经洛索立宾（一种TLR 7激动剂）处理的WT小鼠的全血显示出活化血小板的剂量依赖性增加。在脓毒症小鼠模型中，盲肠结扎穿孔（CLP）后24小时血小板活化和PLA形成显著增加，分别由CD 41 +/CD 62 P+和CD 45 +/CD 62 P+双阳性表达证明。脓毒症诱导的PLA形成在TLR 7 −/−小鼠中显著减弱。最后，在离体实验中，从脓毒症小鼠分离的血浆诱导WT血小板活化，但这种作用在TLR 7缺乏的血小板中显著减弱。这些发现证明了TLR 7信号传导在细菌脓毒症期间血小板活化和PLA形成中的关键作用。
Thrombocytopenia is a common complication in sepsis and is associated with higher mortality. Activated platelets express CD62P, which facilitates platelet-leukocyte aggregate (PLA) formation and contributes to thrombocytopenia in sepsis. We have reported that thrombocytopenia in murine sepsis is partly attributable to TLR7 signaling, but the underlying mechanism is unclear. In the current study, we tested the hypothesis that TLR7 mediates platelet activation and PLA formation during sepsis. In vitro, whole blood from WT mice treated with loxoribine, a TLR7 agonist, exhibited a dose-dependent increase in activated platelets compared to the control (PBS with 0.05% DMSO) or loxoribine-treated TLR7−/− whole blood. In a murine model of sepsis, there was a significant increase in platelet activation and PLA formation 24 hours after cecal ligation and puncture (CLP) as evidenced by double positive expression of CD41+/CD62P+ and CD45+/CD62P+, respectively. The sepsis-induced PLA formation was significantly attenuated in TLR7−/− mice. Finally, in ex-vivo experiments, plasma isolated from septic mice induced WT platelet activation, but such effect was significantly attenuated in platelets deficient of TLR7. These findings demonstrate a pivotal role of TLR7 signaling in platelet activation and PLA formation during bacterial sepsis.
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