Aggravation of viral hepatitis by platelet-derived serotonin
Aggravation of viral hepatitis by platelet-derived serotonin
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DOI：
10.1038/nm1780
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发表时间：
2008-07-01
期刊：
影响因子：
82.9
通讯作者：
Lang, Karl S.
中科院分区：
文献类型：
--
作者：
Lang, Philipp A.;Contaldo, Claudio;Lang, Karl S.
全世界有5亿多人持续感染乙型肝炎病毒或丙型肝炎病毒(1)。尽管这两种病毒的细胞病变性都很差，但任何一种病毒的持续存在都有慢性肝脏炎症的风险，可能导致肝脂肪变性、肝硬化、终末期肝衰竭或肝细胞癌。病毒特异性T细胞是肝炎结局的主要决定因素，因为它们有助于慢性肝炎病毒的早期控制，但它们也介导持续病毒感染期间的免疫病理（1-4）。我们分析了在感染非细胞病变性淋巴细胞性脉络丛脑膜炎病毒的小鼠中，血小板来源的血管活性血清素在病毒诱导的CD8(+) T细胞依赖性免疫病理性肝炎中的作用。病毒感染后，血小板被募集到肝脏，其激活与窦微循环严重减少、病毒消除延迟和免疫病理性肝细胞损伤增加相关。血清素缺乏小鼠缺乏血小板来源的血清素可使肝脏微循环功能障碍正常化，加速肝脏病毒清除，减少CD8(+) T细胞依赖性肝细胞损伤。与这些观察结果一致，血清素治疗感染小鼠延迟了活化的CD8(+) T细胞进入肝脏，延迟了病毒控制并加重了免疫病理性肝炎。因此，血管活性血清素支持病毒在肝脏中的持续存在，并加剧病毒诱导的免疫病理。
More than 500 million people worldwide are persistently infected with hepatitis B virus or hepatitis C virus(1). Although both viruses are poorly cytopathic, persistence of either virus carries a risk of chronic liver inflammation, potentially resulting in liver steatosis, liver cirrhosis, end-stage liver failure or hepatocellular carcinoma. Virus-specific T cells are a major determinant of the outcome of hepatitis, as they contribute to the early control of chronic hepatitis viruses, but they also mediate immunopathology during persistent virus infection(1-4). We have analyzed the role of platelet-derived vasoactive serotonin during virus-induced CD8(+) T cell-dependent immunopathological hepatitis in mice infected with the noncytopathic lymphocytic choriomeningitis virus. After virus infection, platelets were recruited to the liver, and their activation correlated with severely reduced sinusoidal microcirculation, delayed virus elimination and increased immunopathological liver cell damage. Lack of platelet-derived serotonin in serotonin-deficient mice normalized hepatic microcirculatory dysfunction, accelerated virus clearance in the liver and reduced CD8(+) T cell-dependent liver cell damage. In keeping with these observations, serotonin treatment of infected mice delayed entry of activated CD8(+) T cells into the liver, delayed virus control and aggravated immunopathological hepatitis. Thus, vasoactive serotonin supports virus persistence in the liver and aggravates virus-induced immunopathology.