Local Stimulation of Liver Sinusoidal Endothelial Cells with a NOD1 Agonist Activates T Cells and Suppresses Hepatitis B Virus Replication in Mice
Local Stimulation of Liver Sinusoidal Endothelial Cells with a NOD1 Agonist Activates T Cells and Suppresses Hepatitis B Virus Replication in Mice
复制标题
用 NOD1 激动剂局部刺激肝窦内皮细胞可激活 T 细胞并抑制小鼠乙型肝炎病毒复制
DOI：
10.4049/jimmunol.1700921
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发表时间：
2018-05-01
影响因子：
4.4
通讯作者：
Wu, Jun
中科院分区：
文献类型：
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作者：
Huang, Shunmei;Zou, Shi;Wu, Jun
在病毒感染过程中，NOD 1配体（二氨基庚二酸[DAP]）诱导的肝窦内皮细胞（LSEC）功能成熟尚未得到很好的定义。因此，我们研究了DAP刺激的LSEC成熟在B型肝炎病毒（HBV）感染过程中的作用及其在流体动力学注射（HI）小鼠模型中的潜在机制。从野生型C57 BL/6小鼠分离原代LSEC，并在体外和体内用DAP刺激，并通过流式细胞术评估表面标志物的表达以及它们促进T细胞应答的能力。还研究了LSEC成熟对HBV复制和表达的影响以及LSEC在调节其他免疫细胞中的作用。用DAP预处理LSEC诱导T细胞活化。HI给予DAP诱导LSEC成熟，随后增强T细胞应答，这伴随着肝内细胞因子、趋化因子和肝脏中T细胞标志物的产生增加。DAP的HI显著降低小鼠体内HBsAg和HBV DNA水平。重要的是，DAP诱导的抗HBV作用在LSEC耗尽的小鼠中受损，这表明LSEC活化和T细胞募集到肝脏中对于DAP应用介导的抗病毒功能是必需的。总之，结果表明，在小鼠模型中，DAP应用增强了LSEC的Ag呈递能力，这导致增强的T细胞应答并抑制HBV复制。
Functional maturation of liver sinusoidal endothelial cells (LSECs) induced by a NOD1 ligand (diaminopimelic acid [DAP]) during viral infection has not been well defined. Thus, we investigated the role of DAP-stimulated LSEC maturation during hepatitis B virus (HBV) infection and its potential mechanism in a hydrodynamic injection (HI) mouse model. Primary LSECs were isolated from wild-type C57BL/6 mice and stimulated with DAP in vitro and in vivo and assessed for the expression of surface markers as well as for their ability to promote T cell responses via flow cytometry. The effects of LSEC maturation on HBV replication and expression and the role of LSECs in the regulation of other immune cells were also investigated. Pretreatment of LSECs with DAP induced T cell activation in vitro. HI-administered DAP induced LSEC maturation and subsequently enhanced T cell responses, which was accompanied by an increased production of intrahepatic cytokines, chemokines, and T cell markers in the liver. The HI of DAP significantly reduced the HBsAg and HBV DNA levels in the mice. Importantly, the DAP-induced anti-HBV effect was impaired in the LSEC-depleted mice, which indicated that LSEC activation and T cell recruitment into the liver were essential for the antiviral function mediated by DAP application. Taken together, the results showed that the Ag-presenting ability of LSECs was enhanced by DAP application, which resulted in enhanced T cell responses and inhibited HBV replication in a mouse model.