Global miRNA and mRNA expression profiles identify miRNA-26a-2-3p-dependent repression of IFN signature in systemic sclerosis human monocytes
Global miRNA and mRNA expression profiles identify miRNA-26a-2-3p-dependent repression of IFN signature in systemic sclerosis human monocytes
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DOI：
10.1002/eji.201948428
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发表时间：
2020-07-01
影响因子：
5.4
通讯作者：
Maslinski, Wlodzimierz
中科院分区：
文献类型：
--
作者：
Ciechomska, Marzena;Wojtas, Bartosz;Maslinski, Wlodzimierz
单核细胞诱导的I型干扰素及干扰素刺激基因(ISGs)异常是系统性硬化症(SSC)发病的重要特征之一。微小RNA(MiRNA)的异常表达与干扰素的过度产生有关，然而miRNA在SSC单核细胞中的作用在很大程度上仍不清楚。这项研究探索了SSC单核细胞的全局miRNA-mRNA谱以及特定的miRNAs对干扰素和ISGs的功能衰减。同时对健康对照组和SSC单核细胞进行mRNA和miRNA的全局测序。在计算分析之后，选定的miRNAs-mRNA候选被验证，与临床参数相关，并通过功能分析进行测试。转录数据和qPCR分析证实SSC中有干扰素信号，但类风湿关节炎单核细胞中没有。在miRNA-seq分析的基础上，选择了5个miRNA进行进一步验证。仅证实了miRNA-26a-2-3p和miRNA-485-3p的表达模式，并与临床参数呈负相关。在功能分析中，外源性将miRNA-26a-2-3p传递给TLR刺激的单核细胞THP-1细胞特异性地抑制ISGs，但不抑制炎症体活性。综上所述，我们的miRNA-mRNA共测序和功能分析证明miRNA-26a-2-3p是一个新的候选基因，它被预测为负调控ISGs。提示miRNA-26a-2-3的表达减少可能与SSC单核细胞的致病性干扰素信号有关。
Dysregulation in type I IFN and IFN-stimulated genes (ISGs) induced by monocytes is one of the key features of systemic sclerosis (SSc) pathogenesis. Abnormalities in microRNA (miRNA) expression are related to excessive IFN production, however the role of miRNA remains largely elusive in SSc monocytes. This study explores global miRNA-mRNA profiling of SSc monocytes and functional attenuation of IFN and ISGs by specific miRNAs. Global sequencing of mRNA (mRNA-seq) and miRNA (miRNA-seq) samples were performed simultaneously on healthy controls and SSc monocytes. Following computational analysis, selected miRNAs-mRNA candidates were validated, correlated with clinical parameters, and tested by functional assays. Transcriptomics data and qPCR analysis confirmed IFN signature in SSc but not in rheumatoid arthritis monocytes. Based on miRNA-seq analysis, five miRNAs were selected for further validation. Only the expression patterns of miRNA-26a-2-3p and miRNA-485-3p were confirmed and negatively correlated with clinical parameters. Exogenous delivery of miRNA-26a-2-3p to TLR-stimulated monocytic THP-1 cells specifically inhibited ISGs but not inflammasome activity in functional assays. In conclusion, our miRNA-mRNA co-sequencing and functional analysis identify miRNA-26a-2-3p as a new candidate, which is predicated to negatively regulate ISGs. This implies that reduced expression of miRNA-26a-2-3 may be involved in pathogenic IFN signature in SSc monocytes.