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Sirt1 ameliorates systemic sclerosis by targeting the mTOR pathway

  • Author Footnotes
    1 Xiaoxia Zhu and Haiyan Chu contributed equally to this paper.
    Xiaoxia Zhu
    Footnotes
    1 Xiaoxia Zhu and Haiyan Chu contributed equally to this paper.
    Affiliations
    Division of Rheumatology, Huashan Hospital, Fudan University, China

    Institute of Rheumatology, Immunology and Allergy, Fudan University, China
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  • Author Footnotes
    1 Xiaoxia Zhu and Haiyan Chu contributed equally to this paper.
    Haiyan Chu
    Footnotes
    1 Xiaoxia Zhu and Haiyan Chu contributed equally to this paper.
    Affiliations
    Institute of Rheumatology, Immunology and Allergy, Fudan University, China

    Ministry of Education (MOE) Key Laboratory of Contemporary, Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
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  • Shuai Jiang
    Affiliations
    Institute of Rheumatology, Immunology and Allergy, Fudan University, China

    Ministry of Education (MOE) Key Laboratory of Contemporary, Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
    Search for articles by this author
  • Qingmei Liu
    Affiliations
    Institute of Rheumatology, Immunology and Allergy, Fudan University, China

    Division of Dermatology, Huashan Hospital, Fudan University, China
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  • Lei Liu
    Affiliations
    Division of Rheumatology, Huashan Hospital, Fudan University, China

    Institute of Rheumatology, Immunology and Allergy, Fudan University, China
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  • Yu Xue
    Affiliations
    Division of Rheumatology, Huashan Hospital, Fudan University, China

    Institute of Rheumatology, Immunology and Allergy, Fudan University, China
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  • Shucong Zheng
    Affiliations
    Division of Rheumatology, Huashan Hospital, Fudan University, China

    Institute of Rheumatology, Immunology and Allergy, Fudan University, China
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  • Weiguo Wan
    Affiliations
    Division of Rheumatology, Huashan Hospital, Fudan University, China

    Institute of Rheumatology, Immunology and Allergy, Fudan University, China
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  • Jianhua Qiu
    Affiliations
    Department of Emergency Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
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  • Jiucun Wang
    Correspondence
    Corresponding author at: 2005 Songhu Road, Shanghai 200438, China.
    Affiliations
    Institute of Rheumatology, Immunology and Allergy, Fudan University, China

    Ministry of Education (MOE) Key Laboratory of Contemporary, Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
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  • Hejian Zou
    Correspondence
    Corresponding author at: 12 Wulumuqizhong Road, Shanghai 200040, China.
    Affiliations
    Division of Rheumatology, Huashan Hospital, Fudan University, China

    Institute of Rheumatology, Immunology and Allergy, Fudan University, China
    Search for articles by this author
  • Author Footnotes
    1 Xiaoxia Zhu and Haiyan Chu contributed equally to this paper.

      Highlights

      • Sirt1 activation ameliorated cutaneous inflammation and fibrosis in bleomycin induced scleroderma mice.
      • mTOR activation is associated with the pathogenesis of SSc.
      • Inhibition of mTOR pathway activation might be the mechanism of Sirt1 ameliorating SSc.

      Abstract

      Background

      Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by inflammation and fibrosis. Our previous research has indicated that Sirtuin1 (Sirt1) plays a role in the regulation of TNF-α-induced inflammation; however, whether Sirt1 may inhibit the progress of SSc by blocking inflammation remains unknown.

      Objective

      We aimed to investigate the function of Sirt1 in SSc.

      Methods

      The function and its mechanism of Sirt1 were evaluated in fibroblasts or scleroderma mice. The expression of Sirt1 and cytokines was analyzed using real-time PCR, western blot, ELISA and immunohistochemistry.

      Results

      We determined that fibroblasts of SSc patients were activated to exhibit inflammation. Sirt1, activated by resveratrol (Res), ameliorated cutaneous inflammation and fibrosis in bleomycin (BLM)-induced scleroderma mice. An improvement in mammalian target of rapamycin (mTOR) was identified in the fibroblasts of SSc patients and the skin lesions of BLM mice. Rapamycin, an mTOR specific inhibitor, substantially inhibited the induced inflammation and fibrosis. The enhancement of mTOR expression in the skin lesions of the BLM-treated mice was significantly inhibited by Sirt1 activation. However, in both the BLM-treated cells and mice, Res exerted an inhibitory function on the expression of inflammatory factors, and collagen was diminished following mTOR knockdown. These findings suggest that Res may inhibit inflammation and fibrosis via mTOR.

      Conclusion

      The modulation of Sirt1 activity may represent a potential therapeutic method for SSc. The mechanism may involve the inhibition of mTOR phosphorylation, whereas mTOR activity was shown to be a pathogenic culprit of SSc.

      Keywords

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