Department of Experimental Neurology, Charité—Universitätsmedizin Berlin, Berlin, Germany.
Infect Immun. 2011 Feb;79(2):928-36. doi: 10.1128/IAI.00782-10. Epub 2010 Dec 13.
Thrombopoietin (Tpo), which primarily regulates megakaryopoiesis, and its receptor (c-Mpl) are expressed in the brain, where Tpo exhibits proapototic effects on neurons. In the present study, we investigated the implication of Tpo in experimental pneumococcal meningitis. Following intrathecal infection with the encapsulated Streptococcus pneumoniae strain D39, we observed upregulation of Tpo mRNA expression at 12 h and 24 h in brain homogenates of wild-type C57BL/6 mice. c-Mpl mRNA expression was upregulated at 12 h and returned to baseline at 24 h. Compared to wild-type mice, mutants with homozygous Tpo receptor ablation (c-Mpl(-/-)) displayed reduced microglial activation and neuronal apoptosis in the dentate gyrus. Concentrations of bacteria in blood or cerebrospinal fluid (CSF), as well as CSF pleocytosis, were not significantly different between wild-type and c-Mpl(-/-) mice. In human postmortem brain, Tpo protein was colocalized to macrophages during encephalitis. In murine primary microglia and RAW264.7 macrophages, upregulation of Tpo mRNA was induced by D39-conditioned medium but not by bacterial lipopeptide or by medium conditioned by pneumococcal mutants defective in hydrogen peroxide formation (ΔspxB) or pneumolysin (Δpln). We conclude that Tpo acts as a mediator of neuronal damage in bacterial meningitis.
血小板生成素（Tpo）主要调节巨核细胞生成，其受体（c-Mpl）在大脑中表达，Tpo 在大脑中对神经元表现出促凋亡作用。在本研究中，我们研究了 Tpo 在实验性化脓性脑膜炎中的作用。在鞘内感染有荚膜的肺炎链球菌菌株 D39 后，我们观察到野生型 C57BL/6 小鼠大脑匀浆中 Tpo mRNA 表达在 12 小时和 24 小时上调。c-Mpl mRNA 表达在 12 小时上调，并在 24 小时恢复基线。与野生型小鼠相比，Tpo 受体缺失（c-Mpl(-/-)）的突变体中小胶质细胞激活和齿状回神经元凋亡减少。血液或脑脊液（CSF）中的细菌浓度以及 CSF 白细胞增多在野生型和 c-Mpl(-/-) 小鼠之间没有显著差异。在人类死后大脑中，Tpo 蛋白在脑炎期间与巨噬细胞共定位。在原代小鼠小胶质细胞和 RAW264.7 巨噬细胞中，D39 条件培养基诱导 Tpo mRNA 上调，但细菌脂肽或过氧化氢形成缺陷（ΔspxB）或肺炎球菌溶素（Δpln）突变体的条件培养基不诱导 Tpo mRNA 上调。我们得出结论，Tpo 是细菌性脑膜炎中神经元损伤的介导物。
