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Role of STAT3 in skin fibrosis and transforming growth factor beta signalling
Mesias Pedroza1, Sarah To1, Shervin Assassi2
1Department of Medicine, Section of Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, TX, USA.
Objective:
SSc is an autoimmune disease characterized by progressive fibrosis of the skin and internal organs. IL-6 and related cytokines that signal through STAT3 have been implicated in the pathogenesis of SSc and mouse models of fibrosis. The aim of this study was to investigate the efficacy of inhibiting STAT3 in the development of fibrosis in two mouse models of skin fibrosis.
Methods:
Biopsy samples of skin from SSc patients and healthy control subjects were used to determine the expression pattern of phosphotyrosyl (pY705)-STAT3. C188-9, a small molecule inhibitor of STAT3, was used to treat fibrosis in the bleomycin-induced fibrosis model and Tsk-1 mice. In vitro studies were performed to determine the extent to which STAT3 regulates the fibrotic phenotype of dermal fibroblasts.
Results:
Increased STAT3 and pY705-STAT3 was observed in SSc skin biopsies and in both mouse models of SSc. STAT3 inhibition with C188-9 resulted in attenuated skin fibrosis, myofibroblast accumulation, pro-fibrotic gene expression and collagen deposition in both mouse models of skin fibrosis. C188-9 decreased in vitro dermal fibroblast production of fibrotic genes induced by IL-6 trans-signalling and TGF-β. Finally, TGF-β induced phosphotyrosylation of STAT3 in a SMAD3-dependent manner.
Conclusion:
STAT3 inhibition decreases dermal fibrosis in two models of SSc. STAT3 regulates dermal fibroblasts function in vitro and can be activated by TGF-β. These data suggest that STAT3 is a potential therapeutic target for dermal fibrosis in diseases such as SSc.
Insights
STAT3 inhibition effectively reduced skin fibrosis in mouse models of systemic sclerosis (SSc). This suggests STAT3 is a promising therapeutic target for treating dermal fibrosis.
Area of Science:
- Immunology
- Dermatology
- Fibrosis Research
Background:
- Systemic sclerosis (SSc) is an autoimmune disease causing progressive skin and organ fibrosis.
- Signal transducer and activator of transcription 3 (STAT3) signaling is implicated in SSc pathogenesis and fibrosis models.
- Investigating STAT3 inhibition offers a potential therapeutic strategy for SSc-related fibrosis.
Purpose of the Study:
- To evaluate the efficacy of STAT3 inhibition in mitigating skin fibrosis.
- To explore the role of STAT3 in the fibrotic phenotype of dermal fibroblasts.
- To determine if STAT3 activation is linked to fibrotic processes in SSc.
Main Methods:
- Analyzed STAT3 and pY705-STAT3 expression in SSc patient skin biopsies.
- Utilized a small molecule inhibitor (C188-9) targeting STAT3 in bleomycin-induced and Tsk-1 mouse models of skin fibrosis.
- Conducted in vitro studies on dermal fibroblasts to assess STAT3's role in fibrotic gene expression.
Main Results:
- Elevated STAT3 and pY705-STAT3 levels were found in SSc skin and mouse models.
- STAT3 inhibition with C188-9 significantly reduced skin fibrosis, myofibroblast accumulation, and collagen deposition in both models.
- In vitro, C188-9 suppressed IL-6 and TGF-β-induced fibrotic gene production by dermal fibroblasts.
- TGF-β was shown to induce STAT3 phosphotyrosylation in a SMAD3-dependent manner.
Conclusions:
- STAT3 inhibition effectively decreases dermal fibrosis in preclinical SSc models.
- STAT3 plays a crucial role in regulating dermal fibroblast function and fibrotic processes.
- Targeting STAT3 presents a potential therapeutic avenue for managing dermal fibrosis in SSc and related conditions.