Activation of Liver X Receptor α Sensitizes Mice to T-Cell Mediated Hepatitis.
Activation of Liver X Receptor α Sensitizes Mice to T-Cell Mediated Hepatitis.
复制标题
DOI：
10.1002/hep4.1584
复制
发表时间：
2020-11
影响因子：
5.1
通讯作者：
Xie W
中科院分区：
文献类型：
--
作者：
Gao L;Li B;Wang J;Shen D;Yang M;Sun R;Tung HC;Xu M;Ren S;Zhang M;Yang D;Lu B;Wang H;Liu Y;Xie W
自身免疫性肝炎（AIH）是一种肝脏炎症性疾病。肝脏X受体（LXR），包括α和β亚型，以前已知具有抗炎活性。本研究的目的是确定LXR是否以及如何在AIH中发挥作用。使用LXRα功能获得和功能丧失小鼠模型以及伴刀豆球蛋白A（ConA）T细胞介导的肝炎模型。我们首先发现，在ConA肝炎模型和AIH患者中，LXRα的肝脏表达降低。在ConA模型中，我们惊讶地发现，组成性激活的VP-LXRα全身敲入（LXRα-KI）小鼠中LXRα的激活加剧了ConA诱导的AIH，而LXRα−/−小鼠显示ConA诱导的AIH减弱。有趣的是，在脂肪酸结合蛋白-VP ‐LXRα转基因小鼠中，LXRα的肝细胞特异性激活不会加重ConA诱导的肝炎。从机制上讲，LXRα-KI等位基因的致敏作用是恒定的自然杀伤T（iNKT）细胞依赖性的，因为当LXRα-KI等位基因被繁殖到NKT缺陷型CD 1d −/−背景中时，致敏作用被消除。此外，LXRα增强的ConA诱导的肝炎依赖于干扰素γ。相比之下，过继转移从LXRα-KI小鼠分离的肝iNKT细胞足以使CD 1d −/−小鼠对ConA-诱导的AIH敏感。结论：LXRα的激活以iNKT和干扰素γ依赖的方式使小鼠对ConA诱导的AIH增敏。提示LXRα在AIH的发生发展中起重要作用。我们的研究结果表明，LXRα的激活以iNKT依赖性和IFN-γ依赖性的方式使小鼠对ConA诱导的AIH增敏。提示LXRα在AIH的发生发展中起重要作用。
Autoimmune hepatitis (AIH) is an inflammatory disease of the liver. Liver X receptors (LXRs), including the α and β isoforms, are previously known for their anti‐inflammatory activities. The goal of this study is to determine whether and how LXR plays a role in AIH. LXRα gain‐of‐function and loss‐of‐function mouse models were used, in conjunction with the concanavalin A (ConA) model of T‐cell mediated hepatitis. We first showed that the hepatic expression of LXRα was decreased in the ConA model of hepatitis and in human patients with AIH. In the ConA model, we were surprised to find that activation of LXRα in the constitutively activated VP‐LXRα whole‐body knock‐in (LXRα‐KI) mice exacerbated ConA‐induced AIH, whereas the LXRα−/− mice showed attenuated ConA‐induced AIH. Interestingly, hepatocyte‐specific activation of LXRα in the fatty acid binding protein–VP‐LXRα transgenic mice did not exacerbate ConA‐induced hepatitis. Mechanistically, the sensitizing effect of the LXRα‐KI allele was invariant natural killer T (iNKT)–cell dependent, because the sensitizing effect was abolished when the LXRα‐KI allele was bred into the NKT‐deficient CD1d−/− background. In addition, LXRα‐enhanced ConA‐induced hepatitis was dependent on interferon gamma. In contrast, adoptive transfer of hepatic iNKT cells isolated from LXRα‐KI mice was sufficient to sensitize CD1d−/− mice to ConA‐induced AIH. Conclusion: Activation of LXRα sensitizes mice to ConA‐induced AIH in iNKT and interferon gamma–dependent manner. Our results suggest that LXRα plays an important role in the development of AIH. Our results showed that activation of LXRα sensitizes mice to ConA‐induced AIH in an iNKT‐dependent and IFN‐γ‐dependent manner. Our results suggest that LXRα plays an important role in the development of AIH.