Platelets play a role not only in hemostasis and thrombosis, but also in inflammation and innate immunity. We previously reported that an activated form of tyrosyl-tRNA synthetase (YRS ACT ) has an extratranslational activity that enhances megakaryopoiesis and platelet production in mice. Here, we report that YRS ACT mimics inflammatory stress inducing a unique megakaryocyte (MK) population with stem cell (Sca1) and myeloid (F4/80) markers through a mechanism dependent on Toll-like receptor (TLR) activation and type I interferon (IFN-I) signaling. This mimicry of inflammatory stress by YRS ACT was studied in mice infected by lymphocytic choriomeningitis virus (LCMV). Using Sca1/EGFP transgenic mice, we demonstrated that IFN-I induced by YRS ACT or LCMV infection suppressed normal hematopoiesis while activating an alternative pathway of thrombopoiesis. Platelets of inflammatory origin (Sca1/EGFP + ) were a relevant proportion of those circulating during recovery from thrombocytopenia. Analysis of these “inflammatory” MKs and platelets suggested their origin in myeloid/MK-biased hematopoietic stem cells (HSCs) that bypassed the classical MK-erythroid progenitor (MEP) pathway to replenish platelets and promote recovery from thrombocytopenia. Notably, inflammatory platelets displayed enhanced agonist-induced activation and procoagulant activities. Moreover, myeloid/MK-biased progenitors and MKs were mobilized from the bone marrow, as evidenced by their presence in the lung microvasculature within fibrin-containing microthrombi. Our results define the function of YRS ACT in platelet generation and contribute to elucidate platelet alterations in number and function during viral infection.

中文翻译：

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模拟病毒感染的酪氨酰-tRNA 合成酶刺激的炎症性血小板生成

血小板不仅在止血和血栓形成中发挥作用，还在炎症和先天免疫中发挥作用。我们之前报道过一种活化形式的酪氨酰-tRNA 合成酶 (YRS行为) 具有增强小鼠巨核细胞生成和血小板生成的翻译外活性。在这里，我们报告 YRS行为模拟炎症应激，通过依赖于 Toll 样受体 (TLR) 激活和 I 型干扰素 (IFN-I) 信号传导的机制，诱导具有干细胞 (Sca1) 和骨髓 (F4/80) 标记的独特巨核细胞 (MK) 群体。YRS 对炎症应激的这种模仿行为在被淋巴细胞性脉络丛脑膜炎病毒 (LCMV) 感染的小鼠中进行了研究。使用 Sca1/EGFP 转基因小鼠，我们证明了 YRS 诱导的 IFN-I行为或 LCMV 感染抑制了正常的造血功能，同时激活了另一种血小板生成途径。炎症起源的血小板 (Sca1/EGFP+) 是从血小板减少症恢复期间循环的相关比例。对这些“炎症性”MK 和血小板的分析表明，它们起源于骨髓/MK 偏向的造血干细胞 (HSC)，这些造血干细胞绕过了经典的 MK-红细胞祖细胞 (MEP) 途径来补充血小板并促进血小板减少症的恢复。值得注意的是，炎症性血小板显示出增强的激动剂诱导的激活和促凝活性。此外，骨髓/MK 偏向的祖细胞和 MKs 从骨髓中动员起来，正如它们在含有纤维蛋白的微血栓内的肺微血管系统中的存在所证明的那样。我们的结果定义了 YRS 的功能行为在血小板生成中，并有助于阐明病毒感染期间血小板数量和功能的改变。