Sepsis Alters the Megakaryocyte-Platelet Transcriptional Axis Resulting in Granzyme B-mediated Lymphotoxicity
Sepsis Alters the Megakaryocyte-Platelet Transcriptional Axis Resulting in Granzyme B-mediated Lymphotoxicity
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DOI：
10.1164/rccm.200807-1085oc
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发表时间：
2009-03-15
影响因子：
24.7
通讯作者：
Hoffman, Eric P.
中科院分区：
文献类型：
--
作者：
Freishtat, Robert J.;Natale, JoAnne;Hoffman, Eric P.
基本原理：脓毒症相关死亡率的部分原因是免疫缺陷继发于严重的淋巴细胞凋亡。目的：由于最近的证据表明，血小板参与微血管炎症，并在脓毒症淋巴微血管中积累，我们假设血小板在脓毒症相关淋巴细胞凋亡中起直接作用。我们研究了小鼠诱导的脓毒症模型中的巨核细胞和血小板，并在脓毒症儿童中进行了验证，其显示了细胞毒性丝氨酸蛋白酶颗粒酶B的诱导。测量和主要结果：来自脓毒症小鼠的血小板离体诱导健康脾细胞的显著凋亡。脓毒症颗粒酶B null（-/-）小鼠的血小板没有表现出明显的光毒性。结论：我们的研究结果建立了脓毒症的概念进展：脓毒症巨核细胞产生血小板与急性改变的mRNA谱，这些血小板介导的光毒性通过颗粒酶B。鉴于淋巴细胞凋亡对脓毒症相关死亡率的贡献，血小板颗粒酶B的调节成为研究和治疗的重要新靶点。
Rationale: Sepsis-related mortality results in part from immunodeficiency secondary to profound lymphoid apoptosis. The biological mechanisms responsible are not understood.Objectives: Because recent evidence shows that platelets are involved in microvascular inflammation and that they accumulate in lymphoid microvasculature in sepsis, we hypothesized a direct role for platelets in sepsis-related lymphoid apoptosis.Methods: We studied megakaryocytes and platelets from a murine-induced sepsis model, with validation in septic children, which showed induction of the cytotoxic serine protease granzyme B.Measurements and Main Results: Platelets from septic mice induced marked apoptosis of healthy splenocytes ex vivo. Platelets from septic granzyme B null (-/-) mice showed no lymphotoxicity.Conclusions: Our findings establish a conceptual advance in sepsis: Septic megakaryocytes produce platelets with acutely altered mRNA profiles, and these platelets mediate lymphotoxicity via granzyme B. Given the contribution of lymphoid apoptosis to sepsis-related mortality, modulation of platelet granzyme B becomes an important new target for investigation and therapy.