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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Article info
Publication history
Published online: May 03, 2017
Accepted:
April 25,
2017
Received in revised form:
March 26,
2017
Received:
December 3,
2016
Identification
Copyright
© 2017 Published by Elsevier Ireland Ltd on behalf of Japanese Society for Investigative Dermatology.
