C/EBPα/miR-7 Controls CD4+ T-Cell Activation and Function and Orchestrates Experimental Autoimmune Hepatitis in Mice
C/EBPα/miR-7 Controls CD4+ T-Cell Activation and Function and Orchestrates Experimental Autoimmune Hepatitis in Mice
复制标题
C/EBPα/miR-7 控制 CD4 T 细胞活化和功能，并协调小鼠实验性自身免疫性肝炎
DOI：
10.1002/hep.31607
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发表时间：
2021-04-19
期刊：
影响因子：
13.5
通讯作者：
Xu, Lin
中科院分区：
文献类型：
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作者：
Zhao, Juanjuan;Chu, Fengyun;Xu, Lin
背景与目的近年来越来越多的证据表明microRNA-7（miR-7）是一个重要的基因，与包括肝癌在内的多种疾病的发生发展有关。然而，miR-7在自身免疫性肝炎（AIH.Approach and Results）中的作用尚不清楚。在刀豆蛋白A诱导的小鼠急性自身免疫性肝损伤（ALI）模型中，miR-7缺陷导致病理学恶化，并伴有CD 4（+）T细胞的过度活化状态。CD 4（+）T细胞的耗竭降低了miR-7缺陷对ALI病理学的影响。有趣的是，miR-7缺陷在体外增加了CD 4（+）T细胞的活化、增殖和细胞因子的产生。连续性细胞转移实验表明，miR-7（def）CD 4（+）T细胞可加重ALI的病理过程。进一步的分析显示miR-7在活化的CD 4（+）T细胞中表达上调。重要的是，pre-miR-7 b（CD 4（+）T细胞中成熟miR-7的主要来源）的转录主要依赖于转录因子CCAAT增强子结合蛋白α（C/EBP α），其结合miR-7 b基因的核心启动子区。全局基因分析显示，丝裂原活化蛋白激酶4（MAPK 4）是CD 4（+）T细胞中miR-7的靶点。最后，MAPK 4的缺失可以改善有或没有miR-7缺陷的CD 4（+）T细胞的活化状态。我们的研究证明了miR-7在刀豆球蛋白A诱导的AIH中的重要作用。具体来说，我们提供的证据表明，C/EBP α/miR-7轴负控制CD 4（+）T细胞的活化和功能，通过MAPK 4，从而精心策划实验AIH.Conclusions小鼠的miR-7在肝脏相关疾病的重要作用，并揭示了C/EBP α/miR-7轴在CD 4（+）T细胞的生物学功能的免疫介导的肝脏疾病的发病机制的价值。
Background and Aims Increasing evidence in recent years has suggested that microRNA-7 (miR-7) is an important gene implicated in the development of various diseases including HCC. However, the role of miR-7 in autoimmune hepatitis (AIH) is unknown.Approach and Results Herein, we showed that miR-7 deficiency led to exacerbated pathology in Concanavalin-A-induced murine acute autoimmune liver injury (ALI) model, accompanied by hyperactivation state of CD4(+) T cells. Depletion of CD4(+) T cells reduced the effect of miR-7 deficiency on the pathology of ALI. Interestingly, miR-7 deficiency elevated CD4(+) T-cell activation, proliferation, and cytokine production in vitro. Adoptive cell transfer experiments showed that miR-7(def) CD4(+) T cells could exacerbate the pathology of ALI. Further analysis showed that miR-7 expression was up-regulated in activated CD4(+) T cells. Importantly, the transcription of pre-miR-7b, a major resource of mature miR-7 in CD4(+) T cells, was dominantly dependent on transcription factor CCAAT enhancer binding protein alpha (C/EBP alpha), which binds to the core promoter region of the miR-7b gene. Global gene analysis showed that mitogen-activated protein kinase 4 (MAPK4) is a target of miR-7 in CD4(+) T cells. Finally, the loss of MAPK4 could ameliorate the activation state of CD4(+) T cells with or without miR-7 deficiency. Our studies document the important role of miR-7 in the setting of AIH induced by Concanavalin-A. Specifically, we provide evidence that the C/EBP alpha/miR-7 axis negatively controls CD4(+) T-cell activation and function through MAPK4, thereby orchestrating experimental AIH in mice.Conclusions This study expands on the important role of miR-7 in liver-related diseases and reveals the value of the C/EBP alpha/miR-7 axis in CD4(+) T-cell biological function for the pathogenesis of immune-mediated liver diseases.