MicroRNA-351 promotes schistosomiasis-induced hepatic fibrosis by targeting the vitamin D receptor
MicroRNA-351 promotes schistosomiasis-induced hepatic fibrosis by targeting the vitamin D receptor
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MicroRNA-351 通过靶向维生素 D 受体促进血吸虫病诱导的肝纤维化。
DOI：
10.1073/pnas.1715965115
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发表时间：
2018-01-02
影响因子：
11.1
通讯作者：
Pan, Weiqing
中科院分区：
文献类型：
--
作者：
He, Xing;Sun, Yue;Pan, Weiqing
意义 肝纤维化是许多慢性肝病最终常见的病理结果，当肝星状细胞 (HSC) 被激活成为纤维化肌成纤维细胞时就会发生。迄今为止，仍然没有批准的抗纤维化疗法。越来越多的证据表明，针对解除管制的 miRNA 可以减轻疾病结果。在这项研究中，使用经过充分研究的人类血吸虫病模型，我们发现升高的miR-351通过靶向维生素D受体促进感染后HSC的激活，而rAAV8介导的肝脏中miR-351的抑制可通过减轻肝纤维化来保护宿主免受致命感染。该研究深入了解导致血吸虫病相关肝纤维化的机制以及血吸虫病和其他纤维化疾病的干预目标。 microRNA (miRNA) 的异常表达是包括器官纤维化在内的一系列人类疾病的基础，而肝星状细胞 (HSC) 是肝纤维化的主要效应器。在这里，我们发现在血吸虫感染的早期阶段，HSC 中宿主 miR-351 的表达显着降低。然而，该表达在感染后期（感染52天后）显着增加。 miR-351 水平升高通过靶向维生素 D 受体 (VDR)（SMAD 信号传导的拮抗剂）促进肝纤维化。重要的是，使用高亲肝性重组腺相关病毒血清型8（rAAV8）有效且持续地抑制肝组织中的miR-351，减轻了肝纤维化，部分保护宿主免受致命的血吸虫病的侵害。此外，我们发现HSCs感染过程中miR-351受到IFN-γ的负向调节。在感染早期，IFN-γ水平升高，通过信号转导子和转录激活子1的激活以及与前miR-351启动子结合的IFN调节因子2的诱导，抑制HSC中miR-351的表达。我们的研究深入了解了 miR-351 调节血吸虫病肝纤维化的机制，并强调了 rAAV8 介导的 miR-351 抑制作为纤维化疾病治疗干预的潜力。
Significance Hepatic fibrosis is the final common pathological outcome of many chronic liver diseases and occurs when hepatic stellate cells (HSCs) are activated to become fibrogenic myofibroblasts. To date, there are still no approved antifibrotic therapies. Accumulating evidence suggests that targeting the deregulated miRNAs could mitigate disease outcomes. In this study, using a well-studied model of human schistosomiasis, we show that elevated miR-351 promotes the activation of HSCs after infection by targeting the vitamin D receptor, and inhibition of miR-351 in the liver mediated by rAAV8 protects the host from lethal infection by alleviating hepatic fibrosis. This study provides insights into the mechanisms that result in schistosomiasis-related hepatic fibrosis and targets of intervention for schistosomiasis and other fibrotic diseases. Aberrant expression of microRNAs (miRNAs) underlies a spectrum of human diseases including organ fibrosis, and hepatic stellate cells (HSCs) are the main effectors of hepatic fibrosis. Here, we showed that the expression of host miR-351 in HSCs was markedly reduced during the early stage of Schistosoma infection. However, this expression was significantly increased during the later stage of infection (after 52 d of infection). The elevated levels of miR-351 promoted hepatic fibrosis by targeting the vitamin D receptor (VDR), which is an antagonist of SMAD signaling. Importantly, efficient and sustained inhibition of miR-351 in liver tissues using the highly hepatotropic recombinant adeno-associated virus serotype 8 (rAAV8), alleviated the hepatic fibrosis, partially protecting the host from lethal schistosomiasis. In addition, we found that miR-351 is negatively regulated by IFN-γ in HSCs during infection. At the early stage of infection, the elevated levels of IFN-γ inhibited the expression of miR-351 in HSCs through activation of signal transducer and activator of transcription 1 and induction of IFN regulatory factor 2, which binds the promotor of pre–miR-351. Our study provides insights into the mechanisms by which miR-351 regulates schistosomiasis hepatic fibrosis and highlights the potential of rAAV8-mediated miR-351 inhibition as a therapeutic intervention for fibrotic diseases.