Caspase recruitment domain 6 protects against hepatic ischemia/reperfusion injury by suppressing ASK1
Caspase recruitment domain 6 protects against hepatic ischemia/reperfusion injury by suppressing ASK1
复制标题
DOI：
10.1016/j.jhep.2018.06.014
复制
发表时间：
2018-11-01
影响因子：
25.7
通讯作者：
Li, Hongliang
中科院分区：
文献类型：
--
作者：
Qin, Juan-Juan;Mao, Wenzhe;Li, Hongliang
背景和目的：缺血/再灌注（I/R）损伤引起的肝损伤主要是由无菌炎症和肝细胞死亡的复杂相互作用决定的。 Caspase 募集域家族成员 6 (CARD6) 最初被证明在 NF-κ B 激活中发挥重要作用。在我们的初步研究中，CARD6下调与肝移植患者和小鼠模型的肝缺血再灌注损伤密切相关。因此，我们假设CARD6可以预防肝I/R损伤，并研究其潜在的分子机制。方法：对肝细胞特异性Card6敲除小鼠（HKO）、肝细胞特异性过表达CARD6的Card6转基因小鼠（HTG）以及相应的对照小鼠进行部分肝I/R手术。通过检查肝组织学、血清转氨酶、炎症细胞因子/趋化因子、细胞死亡和炎症信号传导来评估肝损伤。在体内和体外探讨CARD6功能的分子机制。结果：与对照小鼠相比，Card6-HTG小鼠的肝损伤减轻，表现为细胞死亡减少、血清转氨酶水平降低、炎症和浸润减少，而Card6-HKO小鼠则具有相反的表型。从机制上讲，ASK1 及其下游效应子 JNK 和 p38 的磷酸化在 Card6-HKO 小鼠的肝脏中增加，但在 Card6-HTG 小鼠的肝脏中受到抑制。此外，ASK1 敲低使 CARD6 缺陷对 NF-kappa B、JNK 和 p38 激活的影响正常化，而 ASK1 过表达消除了 CARD6 的抑制作用。 CARD6 也被证明与 ASK1 相互作用。缺乏与ASK1相互作用能力的突变体CARD6不能抑制ASK1，也不能预防肝缺血再灌注损伤。结论：CARD6是一种新型的肝缺血再灌注损伤保护因子，通过抑制ASK1信号通路来抑制炎症和肝细胞死亡。 (C) 2018 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
Background & Aims: The hepatic injury caused by ischemia/reperfusion (I/R) insult is predominantly determined by the complex interplay of sterile inflammation and liver cell death. Caspase recruitment domain family member 6 (CARD6) was initially shown to play important roles in NF-kappa B activation. In our preliminary studies, CARD6 downregulation was closely related to hepatic I/R injury in liver transplantation patients and mouse models. Thus, we hypothesized that CARD6 protects against hepatic I/R injury and investigated the underlying molecular mechanisms.Methods: A partial hepatic I/R operation was performed in hepatocyte-specific Card6 knockout mice (HKO), Card6 transgenic mice with CARD6 overexpression specifically in hepatocytes (HTG), and the corresponding control mice. Hepatic histology, serum aminotransferases, inflammatory cytokines/chemokines, cell death, and inflammatory signaling were examined to assess liver damage. The molecular mechanisms of CARD6 function were explored in vivo and in vitro.Results: Liver injury was alleviated in Card6-HTG mice compared with control mice as shown by decreased cell death, lower serum aminotransferase levels, and reduced inflammation and infiltration, whereas Card6-HKO mice had the opposite phenotype. Mechanistically, phosphorylation of ASK1 and its downstream effectors JNK and p38 were increased in the livers of Card6-HKO mice but repressed in those of Card6-HTG mice. Furthermore, ASK1 knockdown normalized the effect of CARD6 deficiency on the activation of NF-kappa B, JNK and p38, while ASK1 overexpression abrogated the suppressive effect of CARD6. CARD6 was also shown to interact with ASK1. Mutant CARD6 that lacked the ability to interact with ASK1 could not inhibit ASK1 and failed to protect against hepatic I/R injury.Conclusions: CARD6 is a novel protective factor against hepatic I/R injury that suppresses inflammation and liver cell death by inhibiting the ASK1 signaling pathway. (C) 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.