Xiaoxia Zhu1, Haiyan Chu2, Shuai Jiang2, Qingmei Liu3, Lei Liu1, Yu Xue1, Shucong Zheng1, Weiguo Wan1, Jianhua Qiu4, Jiucun Wang5, Hejian Zou6. 1. Division of Rheumatology, Huashan Hospital, Fudan University, China; Institute of Rheumatology, Immunology and Allergy, Fudan University, China. 2. 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. 3. Institute of Rheumatology, Immunology and Allergy, Fudan University, China; Division of Dermatology, Huashan Hospital, Fudan University, China. 4. Department of Emergency Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. 5. 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. Electronic address: jcwang@fudan.edu.cn. 6. Division of Rheumatology, Huashan Hospital, Fudan University, China; Institute of Rheumatology, Immunology and Allergy, Fudan University, China. Electronic address: hjzou@fudan.edu.cn.
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.
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 sclerodermamice. 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 sclerodermamice. An improvement in mammalian target of rapamycin (mTOR) was identified in the fibroblasts of SSc patients and the skin lesions of BLMmice. 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.
Authors: Anne E Wyman; Trang T T Nguyen; Pratap Karki; Mohan E Tulapurkar; Chen-Ou Zhang; Junghyun Kim; Theresa G Feng; Abdoulaye J Dabo; Nevins W Todd; Irina G Luzina; Patrick Geraghty; Robert F Foronjy; Jeffrey D Hasday; Anna A Birukova; Sergei P Atamas; Konstantin G Birukov Journal: Sci Rep Date: 2020-07-27 Impact factor: 4.379