MicroRNA-125a contributes to elevated inflammatory chemokine RANTES levels via targeting KLF13 in systemic lupus erythematosus

Authors

  • Xia Zhao,

    1. Joint Molecular Rheumatology Laboratory of Institute of Health Sciences and Shanghai Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai Institutes for Biological Sciences, and Chinese Academy of Sciences, Shanghai, China
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    • Drs. Zhao, Tang, and Qu contributed equally to this work.

  • Yuanjia Tang,

    1. Joint Molecular Rheumatology Laboratory of Institute of Health Sciences and Shanghai Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai Institutes for Biological Sciences, and Chinese Academy of Sciences, Shanghai, China
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    • Drs. Zhao, Tang, and Qu contributed equally to this work.

  • Bo Qu,

    1. Joint Molecular Rheumatology Laboratory of Institute of Health Sciences and Shanghai Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai Institutes for Biological Sciences, and Chinese Academy of Sciences, Shanghai, China
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    • Drs. Zhao, Tang, and Qu contributed equally to this work.

  • Huijuan Cui,

    1. Joint Molecular Rheumatology Laboratory of Institute of Health Sciences and Shanghai Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai Institutes for Biological Sciences, and Chinese Academy of Sciences, Shanghai, China
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  • Shujun Wang,

    1. Joint Molecular Rheumatology Laboratory of Institute of Health Sciences and Shanghai Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai Institutes for Biological Sciences, and Chinese Academy of Sciences, Shanghai, China
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  • Lijia Wang,

    1. Joint Molecular Rheumatology Laboratory of Institute of Health Sciences and Shanghai Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai Institutes for Biological Sciences, and Chinese Academy of Sciences, Shanghai, China
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  • Xiaobing Luo,

    1. Joint Molecular Rheumatology Laboratory of Institute of Health Sciences and Shanghai Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai Institutes for Biological Sciences, and Chinese Academy of Sciences, Shanghai, China
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  • Xinfang Huang,

    1. Joint Molecular Rheumatology Laboratory of Institute of Health Sciences and Shanghai Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai Institutes for Biological Sciences, and Chinese Academy of Sciences, Shanghai, China
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  • Jia Li,

    1. Joint Molecular Rheumatology Laboratory of Institute of Health Sciences and Shanghai Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai Institutes for Biological Sciences, and Chinese Academy of Sciences, Shanghai, China
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  • Shunle Chen,

    1. Joint Molecular Rheumatology Laboratory of Institute of Health Sciences and Shanghai Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai Institutes for Biological Sciences, and Chinese Academy of Sciences, Shanghai, China
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  • Nan Shen

    Corresponding author
    1. Joint Molecular Rheumatology Laboratory of Institute of Health Sciences and Shanghai Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai Institutes for Biological Sciences, and Chinese Academy of Sciences, Shanghai, China
    • Department of Rheumatology, Renji Hospital, Shanghai JiaoTong University School of Medicine, 145 Shan Dong Road (Central), Shanghai 200001, China
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Abstract

Objective

MicroRNA (miRNA) have received increasing attention as posttranscriptional regulators that fine-tune the homeostasis of the inflammatory response. This study aimed to clarify whether miR-125a, which was identified in a pilot expression profiling step, is involved in the inflammatory chemokine pathway in systemic lupus erythematosus (SLE).

Methods

Independent verification of miR-125a expression in amplified samples from SLE patients and normal controls was performed by TaqMan quantitative polymerase chain reaction (PCR) analysis. A combination of 3 bioinformatic prediction techniques and reporter gene assays was used to identify miR-125a targets. In vitro systems of overexpression by transfection and inducible expression by stimulation were performed to investigate the function of miR-125a, which was followed by real-time quantitative PCR and enzyme-linked immunosorbent assay.

Results

In SLE patients, the expression of miR-125a was reduced and the expression of its predicted target gene, KLF13, was increased. Bioinformatics predicted that miR-125a base-paired with sequences in the 3′-untranslated region of KLF13. Overexpression of miR-125a led to a significant reduction in the expression of RANTES and KLF13. MicroRNA-125a inhibited endogenous KLF13 expression in a dose-dependent manner, as determined using gain- and loss-of-function methods. A luciferase reporter system confirmed the miR-125a binding sites. Notably, miR-125a expression was induced in T cells in a dose- and time-dependent manner. Finally, the introduction of miR-125a into T cells from SLE patients alleviated the elevated RANTES expression.

Conclusion

MicroRNA-125a negatively regulates RANTES expression by targeting KLF13 in activated T cells. The underexpression of miR-125a contributes to the elevated expression of RANTES in SLE. Our findings extend the role of miRNA in the pathogenesis of lupus and provide potential strategies for therapeutic intervention.

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