Divergent Roles of Kupffer Cell TLR2/3 Signaling in Alcoholic Liver Disease and the Protective Role of EGCG
Divergent Roles of Kupffer Cell TLR2/3 Signaling in Alcoholic Liver Disease and the Protective Role of EGCG
复制标题
库普弗细胞 TLR2/3 信号传导在酒精性肝病中的不同作用以及 EGCG 的保护作用
DOI：
10.1016/j.jcmgh.2019.09.002
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发表时间：
2020-01-01
影响因子：
7.2
通讯作者：
Wang, Hua
中科院分区：
文献类型：
--
作者：
Luo, Pingping;Wang, Fei;Wang, Hua
背景与目的：Toll样受体2（TLR 2）和TLR 3在病理条件下调节肝脏免疫，但其在酒精性肝病（ALD）中的功能和潜在的药物靶点仍知之甚少。TLR 2基因敲除可诱导ALD相关肝损伤图1显示了通过乙醇攻击与或不与表没食子儿茶素-3-没食子酸酯（EGCG）共施用的TLR 2（-/-））、TLR 3（-/-）、TLR 2（-/-）骨髓移植（BMT）、TLR 3（-/-）BMT、IL-10（-/-）小鼠及其野生型同窝出生小鼠。结果：Toll样受体2和Toll样受体3的缺失分别显著减轻和加重了ALD引起的肝损伤。从机制上讲，枯否细胞失活，M1到M2极化，IL-10的生产，通过STAT 3激活有助于肝保护介导的同时TLR 2抑制和TLR 3激动。这些发现在TLR 2和TLR 3 BMT小鼠中得到进一步证实。我们还鉴定了一种新的ALD保护剂EGCG，其直接与Kupffer细胞TLR 2/3相互作用以诱导IL-10的产生。IL-10的缺乏加重ALD损伤和钝化EGCG介导的肝保护，而枯否细胞的耗尽部分恢复肝损伤，但废除EGCG的actions.CONCLUSIONS：总之，我们的研究结果说明了不同的作用枯否细胞TLR 2/3在ALD进展通过抗炎细胞因子IL-10的生产。
BACKGROUND & AIMS: Toll-like receptor 2 (TLR2) and TLR3 regulate hepatic immunity under pathological conditions, but their functions and potential drug targets in alcoholic liver disease (ALD) remain poorly understood.METHODS: ALD-associated liver injury were induced in TLR2 knockout (TLR2(-/-)), TLR3(-/-), TLR2(-/-) bone marrow transplanted (BMT), TLR3(-/-) BMT, IL-10(-/-) mice, and their wild-type littermates through ethanol challenge with or without co-administered epigallocatechin-3-gallate (EGCG). Moreover, Kupffer cells were depleted by GdCl3 injection to evaluate their pathogenic roles in ALD.RESULTS: We identified that deficiency of TLR2 and TLR3 significantly alleviated and aggravated ALD-induced liver injury, respectively. Mechanistically, Kupffer cell inactivation, M1 to M2 polarization, and IL-10 production via STAT3 activation contributed to hepatic protection mediated by concurrent TLR2 inhibition and TLR3 agonism. These findings were further confirmed in TLR2 and TLR3 BMT mice. We also identified a novel ALD-protective agent EGCG which directly interacted with Kupffer cell TLR2/3 to induce IL-10 production. Deficiency of IL-10 aggravated ALD injury and blunted EGCGmediated hepatoprotection while depletion of Kupffer cells partially recovered liver injury but abolished EGCG's actions.CONCLUSIONS: Altogether, our results illustrate the divergent roles of Kupffer cells TLR2/3 in ALD progression via anti-inflammatory cytokine IL-10 production.