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Aryl hydrocarbon receptor signaling activation in systemic sclerosis attenuates collagen production and is a
Yaqian Shi1, Bingsi Tang1, Jiangfan Yu1
1Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha 410000, Hunan, China; Hunan Key Laboratory of Medical Epigenetics, Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha 410000, Hunan, China.
Abstract:
Systemic sclerosis (SSc) is a systemic autoimmune disease that often leads to fibrosis of multiple organs, and there are no effective treatments. Aryl hydrocarbon receptor (AhR) is a highly evolutionarily conserved transcription factor activated by endogenous and exogenous ligands and that regulate cell proliferation, tumorigenesis and immune balance. Recently, it have reported AhR signaling may participate in fibrosis process, usually consider as a negative regulator of TGF-β. However, the detailed relationship between AhR and SSc has not been reported yet. Here we firstly found that AhR and CYP1A1 downregulated in SSc fibroblast(n = 6). The AhR ligand-Ficz negatively regulates TGF-β1, COL1A1 and α-SMA expression, also enhances the MMP-1 expression via the AhR signaling activation. Conversely the AhR antagonist CH223191 could inhibit this effect. Furthermore, the antifibrosis effect of AhR signaling activation was also confirmed in bleomycin induced scleroderma mouse model. In conclusion, AhR signaling activation balances the extracellular matrix (ECM) composition and deposition, which may provide a new sight to the pathogenesis of SSc and AhR signaling activation may be a potential therapy for SSc.
Insights
Aryl hydrocarbon receptor (AhR) signaling activation may treat systemic sclerosis (SSc). AhR activation downregulates fibrosis markers and balances extracellular matrix, offering a new therapeutic approach for SSc.
Area of Science:
- Immunology
- Dermatology
- Pharmacology
Background:
- Systemic sclerosis (SSc) is an autoimmune disease causing organ fibrosis with no effective treatments.
- Aryl hydrocarbon receptor (AhR) is a transcription factor involved in cell proliferation, immune balance, and potentially fibrosis.
- The specific role of AhR in SSc pathogenesis remains largely unexplored.
Purpose of the Study:
- To investigate the role of AhR signaling in systemic sclerosis (SSc).
- To determine if AhR activation can modulate fibrotic processes in SSc.
- To explore AhR signaling as a potential therapeutic target for SSc.
Main Methods:
- Analysis of AhR and CYP1A1 expression in SSc fibroblasts.
- Treatment of SSc fibroblasts with an AhR ligand (Ficz) and antagonist (CH223191).
- Assessment of extracellular matrix (ECM) component gene expression (TGF-β1, COL1A1, α-SMA, MMP-1).
- Evaluation of AhR signaling in a bleomycin-induced mouse model of scleroderma.
Main Results:
- AhR and CYP1A1 were found to be downregulated in SSc fibroblasts.
- AhR activation by Ficz reduced TGF-β1, COL1A1, and α-SMA expression while increasing MMP-1.
- AhR antagonist CH223191 reversed the effects of Ficz.
- AhR signaling activation demonstrated an antifibrotic effect in a mouse model of scleroderma.
Conclusions:
- AhR signaling activation plays a crucial role in balancing ECM composition and deposition in SSc.
- AhR signaling activation may represent a novel therapeutic strategy for treating systemic sclerosis.
- This study provides new insights into the pathogenesis of SSc and the potential of AhR as a therapeutic target.
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