MicroRNA-302d targets IRF9 to regulate the IFN-induced gene expression in SLE
MicroRNA-302d targets IRF9 to regulate the IFN-induced gene expression in SLE
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DOI：
10.1016/j.jaut.2017.03.003
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发表时间：
2017-05-01
影响因子：
12.8
通讯作者：
Jefferies, Caroline A.
中科院分区：
文献类型：
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作者：
Smith, Siobhan;Fernando, Thilini;Jefferies, Caroline A.
系统性红斑狼疮（SLE）是一种复杂的疾病，它是I型干扰素（IFN）系统过度激活的结果，这是目前针对IFN- α的多种生物疗法的一个特征。我们已经确定了一种雌激素调节的microRNA miR-302d，其在SLE患者单核细胞中的表达降低，并确定其靶点为干扰素调节因子(IRF)-9，这是调节干扰素刺激基因（ISGs）表达的转录复合体的关键成分。与SLE患者单核细胞中miR-302d的表达降低一致，IRF9水平升高，包括MX1和OAS1在内的许多isg的表达也升高。体内评估显示，miR-302d通过靶向IRF9和ISG表达来保护小鼠免受前列腺素诱导的炎症。重要的是，疾病活动性增强的患者miR-302d表达显著降低，IRF9和ISG表达增强，miR-302d与IFN评分呈负相关。总之，这些发现确定miR-302d是I型IFN驱动基因表达的关键调节剂，通过其靶向IRF9和调节ISG表达的能力，强调了非编码RNA在调节SLE中IFN通路中的重要性。(C) 2017年作者。Elsevier Ltd.出版。
Systemic lupus erythematosus (SLE) is a complex disease targeting multiple organs as a result of over activation of the type I interferon (IFN) system, a feature currently being targeted by multiple biologic therapies against IFN-alpha. We have identified an estrogen-regulated microRNA, miR-302d, whose expression is decreased in SLE patient monocytes and identify its target as interferon regulatory factor (IRF)-9, a critical component of the transcriptional complex that regulates expression of interferon stimulated genes (ISGs). In keeping with the reduced expression of miR-302d in SLE patient monocytes, IRF9 levels were increased, as was expression of a number of ISGs including MX1 and OAS1. In vivo evaluation revealed that miR-302d protects against pristane-induced inflammation in mice by targeting IRF9 and hence ISG expression. Importantly, patients with enhanced disease activity have markedly reduced expression of miR-302d and enhanced IRF9 and ISG expression, with miR-302d negatively correlating with IFN score. Together these findings identify miR-302d as a key regulator of type I IFN driven gene expression via its ability to target IRF9 and regulate ISG expression, underscoring the importance of non-coding RNA in regulating the IFN pathway in SLE. (C) 2017 The Authors. Published by Elsevier Ltd.