ATRA ameliorates fibrosis by suppressing the pro-fibrotic molecule Fra2/AP-1 in systemic sclerosis

Zixin Pi; Jiani Liu; Yangfan Xiao; Xinglan He; Ruixuan Zhu; Rui Tang; Xiangning Qiu; Yi Zhan; Zhuotong Zeng; Yaqian Shi; Rong Xiao

doi:10.1016/j.intimp.2023.110420

ATRA ameliorates fibrosis by suppressing the pro-fibrotic molecule Fra2/AP-1 in systemic sclerosis

Int Immunopharmacol. 2023 Aug:121:110420. doi: 10.1016/j.intimp.2023.110420. Epub 2023 Jun 16.

Authors

Zixin Pi¹, Jiani Liu², Yangfan Xiao³, Xinglan He², Ruixuan Zhu², Rui Tang⁴, Xiangning Qiu², Yi Zhan², Zhuotong Zeng⁵, Yaqian Shi⁶, Rong Xiao⁷

Affiliations

¹ Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Hunan Key Laboratory of Medical Epigenetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.; Department of Medical Genetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
² Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Hunan Key Laboratory of Medical Epigenetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
³ Clinical Nursing Teaching and Research Section, Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
⁴ Department of Rheumatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
⁵ Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Hunan Key Laboratory of Medical Epigenetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.. Electronic address: zengzhuotong@csu.edu.cn.
⁶ Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Hunan Key Laboratory of Medical Epigenetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.. Electronic address: shiyaqian@csu.edu.cn.
⁷ Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Hunan Key Laboratory of Medical Epigenetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.. Electronic address: xiaorong65@csu.edu.cn.

PMID: 37331293
DOI: 10.1016/j.intimp.2023.110420

Abstract

Systemic sclerosis (SSc) is an autoimmune connective tissue disease that leads to irreversible fibrosis of the skin and the internal organs. The etiology of SSc is complex, its pathophysiology is poorly understood, and clinical therapeutic options are restricted. Thus, research into medications and targets for treating fibrosis is essential and urgent. Fos-related antigen 2 (Fra2) is a transcription factor that is a member of the activator protein-1 family. Fra2 transgenic mice were shown to have spontaneous fibrosis. All-trans retinoic acid (ATRA) is a vitamin A intermediate metabolite and ligand for the retinoic acid receptor (RAR), which possesses anti-inflammatory and anti-proliferative properties. Recent research has demonstrated that ATRA also has an anti-fibrotic effect. However, the exact mechanism is not fully understood. Interestingly, we identified potential binding sites for the transcription factor RARα to the promoter region of the FRA2 gene through JASPAR and PROMO databases. In this study, the pro-fibrotic effect of Fra2 in SSc is confirmed. SSc dermal fibroblasts and bleomycin-induced fibrotic tissues of SSc animals exhibit increased levels of Fra2. Inhibition of Fra2 expression in SSc dermal fibroblasts with Fra2 siRNA markedly decreased collagen I expression. ATRA reduced the expressions of Fra2, collagen I, and α-smooth muscle actin(α-SMA) in SSc dermal fibroblasts and bleomycin-induced fibrotic tissues of SSc mice. In addition, chromatin immunoprecipitation and dual-luciferase assays demonstrated that retinoic acid receptor RARα binds to the FRA2 promoter and modulates its transcriptional activity. ATRA decreases collagen I expression both in vivo and in vitro via the reduction of Fra2 expression. This work establishes the rationale for expanding the use of ATRA in the treatment of SSc and indicates that Fra2 can be used as an anti-fibrotic target.

Keywords: All-trans retinoic acid; Fibrosis; Fos-related antigen 2; Retinoic acid receptor; Systemic sclerosis.

MeSH terms

Animals
Bleomycin / metabolism
Collagen Type I / metabolism
Disease Models, Animal
Fibroblasts
Fibrosis
Mice
Mice, Transgenic
Receptors, Retinoic Acid / metabolism
Scleroderma, Systemic* / metabolism
Skin / pathology
Transcription Factor AP-1* / metabolism
Tretinoin / pharmacology

Substances

Transcription Factor AP-1
Collagen Type I
Tretinoin
Receptors, Retinoic Acid
Bleomycin