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.

中文翻译：

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全局miRNA和mRNA表达谱确定了系统性硬化症人类单核细胞中干扰素签名的miRNA-26a-2-3p依赖性抑制。

单核细胞诱导的I型IFN和IFN刺激基因（ISG）失调是系统性硬化（SSc）发病机制的关键特征之一。microRNA（miRNA）表达异常与过多的IFN产生有关，但是miRNA的作用在SSc单核细胞中仍然难以捉摸。这项研究探索了SSc单核细胞的全球miRNA-mRNA谱图以及特定miRNA对IFN和ISG的功能衰减。在健康对照和SSc单核细胞上同时进行了mRNA（mRNA-seq）和miRNA（miRNA-seq）样品的全局测序。经过计算分析，选定的miRNAs-mRNA候选物经过验证，与临床参数相关，并通过功能测定进行测试。转录组学数据和qPCR分析证实了SSc中的IFN签名，但类风湿关节炎单核细胞中却没有。基于miRNA-seq分析，选择了五个miRNA进行进一步验证。仅证实了miRNA‐26a‐2‐3‐p和miRNA‐485‐3p的表达模式，并且与临床参数呈负相关。在功能测定中，将miRNA‐26a‐2‐3p外源递送至TLR刺激的单核THP‐1细胞可特异性抑制ISG，但不抑制炎症小体活性。总而言之，我们的miRNA–mRNA共测序和功能分析确定了miRNA‐26a‐2‐3p是新的候选对象，可对ISG产生负调控作用。这意味着miRNA‐26a‐2‐3的表达降低可能与SSc单核细胞的致病性IFN信号有关。在功能测定中，将miRNA‐26a‐2‐3p外源递送至TLR刺激的单核THP‐1细胞可特异性抑制ISG，但不抑制炎症小体活性。总而言之，我们的miRNA–mRNA共测序和功能分析确定了miRNA‐26a‐2‐3p是新的候选对象，可对ISG产生负调控作用。这意味着miRNA‐26a‐2‐3的表达降低可能与SSc单核细胞的致病性IFN信号有关。在功能测定中，将miRNA‐26a‐2‐3p外源递送至TLR刺激的单核THP‐1细胞可特异性抑制ISG，但不抑制炎症小体活性。总而言之，我们的miRNA–mRNA共测序和功能分析确定了miRNA‐26a‐2‐3p是新的候选对象，可对ISG产生负调控作用。这意味着miRNA‐26a‐2‐3的表达降低可能与SSc单核细胞的致病性IFN信号有关。