美国著名杂志指出microRNA在sle发病中的作用

ARTHRITIS & RHEUMATISM：microRNA在系统性红斑狼疮发病中的作用

　　风湿病学领域最有影响力的杂志ARTHRITIS & RHEUMATISM在2009年4月发表了健康所临床课题组沈南研究员的最新研究成果，该项研究首次阐明了miRNA作为负反馈调节分子在狼疮关键致病通路中起了重要作用。ARTHRITIS & RHEUMATISM同期发表了著名自身免疫病学权威Edward K. L. Chan教授撰写的特约评论，他评述这项工作揭示了miRNA参与狼疮发病的新机制，为今后发展miRNA为靶点的干预治疗提供了重要依据。

　　系统性红斑狼疮（systemic lupus erythematosus， SLE） 发病机理复杂，被认为是自身免疫病的原型，I型干扰素通路的异常活化在SLE的发病中起着重要作用。microRNA（miRNA）是近年来广为关注的重要的基因表达调控因子，已有证据表明其在先天免疫应答及炎症因子的信号传导过程中起着重要的负调节作用。红斑狼疮病人干扰素通路异常活化可能与某些miRNA异常表达有关。为探索这一关键问题，沈南组建立了高通量、稳定性好、敏感性和特异性高的miRNA表达谱分析平台，应用这一平台研究了SLE患者、正常人和对照疾病组的外周血白细胞的miRNA表达谱特征，发现一组SLE疾病特异性异常表达的miRNAs，包括已知参与免疫调节的miR-146a在SLE患者中表达不足。

　　研究人员扩大样本进一步探索miR-146a的表达与疾病临床表型的相关性，发现在SLE患者中miR-146a的表达水平与疾病的活动性以及干扰素通路的激活程度呈负相关，还与肾脏受累程度相关。这提示miR-146a可作为SLE的一个新的生物标志物。一系列实验证实miR-146a既能调节Ⅰ型IFN的产生，又能调节Ⅰ型IFN的下游通路。在SLE患者中，miR-146a表达不足导致其调节的多个靶蛋白（TRAF6， IRAK1， IRF5和STAT1）的异常累积，导致活化信号的级联放大，从而对SLE病人体内干扰素通路异常激活有贡献。Faculty of 1000 medicine 对这篇文章进行了评述，该项研究表明miR-146a有望成为调控SLE患者的干扰素通路的新靶点，改变SLE患者体内miR-146a表达水平可作为潜在的治疗手段。相关研究成果已申请国际国内专利。

　　该项工作得到国家科技部、国家自然科学基金和上海市科委的经费支持。

原始出处：

ARTHRITIS & RHEUMATISM Volume 60 Issue 4, Pages 1065 - 1075

MicroRNA-146a contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins

Yuanjia Tang 1, Xiaobing Luo 1, Huijuan Cui 1, Xuming Ni 1, Min Yuan 1, Yanzhi Guo 1, Xinfang Huang 1, Haibo Zhou 1, Niek de Vries 2, Paul Peter Tak 2, Shunle Chen 1, Nan Shen 1 *

1Joint Molecular Rheumatology Laboratory of the Institute of Health Sciences and Shanghai Renji Hospital, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiaotong University School of Medicine, Shanghai, China
2Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Objective

MicroRNA have recently been identified as regulators that modulate target gene expression and are involved in shaping the immune response. This study was undertaken to investigate the contribution of microRNA-146a (miR-146a), which was identified in the pilot expression profiling step, to the pathogenesis of systemic lupus erythematosus (SLE).

Methods

TaqMan microRNA assays of peripheral blood leukocytes were used for comparison of expression levels of microRNA between SLE patients and controls. Transfection and stimulation of cultured cells were conducted to determine the biologic function of miR-146a. Bioinformatics prediction and validation by reporter gene assay and Western blotting were performed to identify miR-146a targets.

Results

Profiling of 156 miRNA in SLE patients revealed the differential expression of multiple microRNA, including miR-146a, a negative regulator of innate immunity. Further analysis showed that underexpression of miR-146a negatively correlated with clinical disease activity and with interferon (IFN) scores in patients with SLE. Of note, overexpression of miR-146a reduced, while inhibition of endogenous miR-146a increased, the induction of type I IFNs in peripheral blood mononuclear cells (PBMCs). Furthermore, miR-146a directly repressed the transactivation downstream of type I IFN. At the molecular level, miR-146a could target IFN regulatory factor 5 and STAT-1. More importantly, introduction of miR-146a into the patients' PBMCs alleviated the coordinate activation of the type I IFN pathway.

Conclusion

The microRNA miR-146a is a negative regulator of the IFN pathway. Underexpression of miR-146a contributes to alterations in the type I IFN pathway in lupus patients by targeting the key signaling proteins. The findings provide potential novel strategies for therapeutic intervention.

　　来源：中科院