期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2212659119
关键词
tyrosyl-tRNA synthetase; megakaryocyte; platelet; inflammatory stress; viral infection
资金
- National Institutes of Health [HL129011, HL135294, AI145374, GM125908, NS113583, GM139627]
- MERU Foundation (Italy)
- National Foundation for Cancer Research
Platelets play a crucial role in hemostasis, thrombosis, inflammation, and innate immunity. A study found that an activated form of tyrosyl-tRNA synthetase (YRSACT) has extratranslational activity that enhances megakaryopoiesis and platelet production. This study discovered that YRSACT can mimic inflammatory stress and induce a unique population of megakaryocytes with stem cell and myeloid markers, relying on Toll-like receptor activation and type I interferon signaling.
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 (YRSACT) has an extratranslational activity that enhances megakaryopoiesis and platelet production in mice. Here, we report that YRSACT 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 YRSACT was studied in mice infected by lymphocytic choriomeningitis virus (LCMV). Using Sca1/EGFP transgenic mice, we demonstrated that IFN-I induced by YRSACT 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 YRSACT in platelet generation and contribute to elucidate platelet alterations in number and function during viral infection.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据