Regulatory T cells suppress sickness behaviour development without altering liver injury in cholestatic mice
Regulatory T cells suppress sickness behaviour development without altering liver injury in cholestatic mice
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DOI：
10.1016/j.jhep.2011.09.014
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发表时间：
2012-03-01
影响因子：
25.7
通讯作者：
Swain, Mark G.
中科院分区：
文献类型：
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作者：
Nguyen, Kimchi;D'Mello, Charlotte;Swain, Mark G.
背景与目的：胆汁淤积性肝脏疾病通常伴有使人衰弱的症状，统称为疾病行为。调节性T细胞（T-T细胞）可以抑制炎症，但是，T-T细胞在调节疾病behaviors.Methods的作用尚未评估：胆汁淤积性肝损伤由于胆管结扎（BDL）的小鼠模型被用来研究T-T细胞在疾病behaviorsdevelopment.Results的作用：BDL小鼠开发可重复的疾病行为，作为评估的社会调查范式，其特征在于减少社会调查行为和增加不动性。BDL小鼠外周T-β的耗竭恶化了BDL相关的疾病行为，而T-β的输注改善了这些行为;然而，肝损伤的严重程度并没有被T-β操纵改变。与对照小鼠相比，BDL小鼠的肝脏IL-6 mRNA和循环IL-6水平升高，并且在T-reg耗尽的BDL小鼠中进一步升高，但在BDL小鼠中输注T-reg后降低。与野生型BDL小鼠相比，IL-6敲除（KO）BDL小鼠表现出疾病行为的显著减少。此外，注射rmIL-6的IL-6 KO BM小鼠显示出与野生型BDL小鼠相似的疾病行为，而盐水注射没有改变IL-6 KO BDL小鼠的行为。BDL与增加海马脑内皮细胞p-STAT 3的表达，这是显着减少IL-6 KO BDL mice.Conclusions：T-STAT调节疾病的行为发展的胆汁淤积性肝损伤的设置，主要通过T-reg抑制循环单核细胞和肝脏IL-6的生产，并通过循环IL-6的作用在脑内皮细胞水平的后续信号。(C)2011年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Cholestatic liver diseases are commonly accompanied by debilitating symptoms, collectively termed sickness behaviours. Regulatory T cells (T-regs) can suppress inflammation; however, a role for T-regs in modulating sickness behaviours has not been evaluated.Methods:A mouse model of cholestatic liver injury due to bile duct ligation (BDL) was used to study the role of T-regs in sickness behaviour development.Results: BDL mice developed reproducible sickness behaviours, as assessed in a social investigation paradigm, characterized by decreased social investigative behaviour and increased immobility. Depletion of peripheral T-regs in BDL mice worsened BDL-associated sickness behaviours, whereas, infusion of T-regs improved these behaviours; however, liver injury severity was not altered by T-regs manipulation. Hepatic IL-6 mRNA and circulating IL-6 levels were elevated in BDL vs. control mice, and were elevated further in T-reg-depleted BDL mice, but were decreased after infusion of T-regs in BDL mice. IL-6 knock out (KO) BDL mice exhibited a marked reduction in sickness behaviours, compared to wildtype BDL mice. Furthermore, IL-6 KO BM, mice injected with rmIL-6 displayed sickness behaviours similar to wildtype BDL mice, whereas saline injection did not alter behaviour in IL-6 KO BDL mice. BDL was associated with increased hippocampal cerebral endothelial cell p-STAT3 expression, which was significantly reduced in IL-6 KO BDL mice.Conclusions: T-regs modulate sickness behaviour development in the setting of cholestatic liver injury; driven mainly through T-reg inhibition of circulating monocyte and hepatic 1L-6 production, and subsequent signalling via circulating 1L-6 acting at the level of the cerebral endothelium. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.