Metformin attenuates bleomycin-induced scleroderma by regulating the balance of Treg/Teff cells and reducing spleen germinal center formation. (October 2019)

• Record Type: Journal Article
• Authors: Wang, Yanlin; Zhang, Shulan; Liang, Zhaojun; Feng, Min; Zhao, Xiangcong; Qin, Kaili; Gao, Chong; Li, Xiaofeng; Guo, Hui; Luo, Jing
• Is Part Of: Molecular immunology. Volume 114(2019:Oct.)
• Page Start: 72
• Page End: 80
• Publication Date: 2019-10
• Subjects: MET metformin -- BLM bleomycin -- Treg cell Regulatory T cell -- GC Germinal center -- Th17 cell T helper 17 cell -- N.S. normal saline -- FCM flow cytometry -- IHC immunohistochemistry -- HYP hydroxyproline -- RT-qPCR real-time quantitative polymerase chain reaction -- IL-17A interleukin-17A -- RORγt retinoic-acid-receptor related orphan receptors gamma t -- Foxp3 forkhead box protein 3 -- p-AMPK phosphorylated AMP-activated protein kinase -- mTOR mammalian target of rapamycin -- Tfh follicular helper T -- SSc systemic sclerosis -- H&E hematoxylin and eosin -- α-SMA α-smooth muscle actin -- PBMC peripheral blood mononuclear cells -- PMA phorbol-12-myristate-13-acetate -- ANOVA one-way analysis of variance -- EndoMT endothelial-to-mesenchymal transition -- TGF transforming growth factor -- ECM extracellular matrix -- HIF hypoxia-induced factor -- STAT signal transducers and activators of transcription -- Ab antibody; Metformin -- Scleroderma -- Effector T cells -- Regulatory T cells -- Germinal center formation; Immunochemistry -- Periodicals; Molecular biology -- Periodicals; Immunochemistry -- Periodicals; Allergy and Immunology -- Periodicals; Molecular Biology -- Periodicals; Immunochimie -- Périodiques; Biologie moléculaire -- Périodiques; Immunochemistry; Molecular biology; Periodicals; Electronic journals; 571.96
• DOI: 10.1016/j.molimm.2019.07.002
• Languages: English
• ISSNs: 0161-5890

Abstract

Highlights: Skin thickness and collagen deposition were decreased by metformin in BLM-induced mice. Metformin significantly alleviated collagen-like deposition. Metformin restored the balance of Th17 and Treg cells in the BLM-induced mice. Abstract: Scleroderma is an inflammatory autoimmune disease characterized by extensive tissue fibrosis. The imbalance of effector T (Teff) and regulatory T (Treg) cells and the production of autoantibodies contribute to the pathogenesis of this disease. Metformin (MET) has anti-inflammatory and anti-fibrotic effects, but its effect on the in vivo pathogenesis of scleroderma remains unknown. Therefore, we investigated the potential therapeutic effects of MET treatment of mice with bleomycin (BLM)-induced scleroderma. Scleroderma was induced in female C57BL mice by daily subcutaneous injections of BLM for 28 days. After each 2 h BLM injection, mice received MET (200, 100 or 50 mg/kg) or saline (control) by intraperitoneal injection. At the end of the fourth week, spleen mononuclear cells were collected for flow cytometry analysis. Skin samples were harvested for immunohistochemistry and quantification of other biological parameters.Our results showed that BLM increased dermal thickness, collagen deposition, and hydroxyproline level, and MET markedly mitigated these effects. MET also restored the Treg/Teff cell balance. Accordingly, the level of IL-17A and RORγt (related to Th17 cells) decreased, but Foxp3 (related to Treg function) increased in a dose-dependent manner. In addition, MET treatment inhibited spleen germinal center formation. These results indicate that the immunomodulatory and anti-fibrosis effects of MET on BLM-induced scleroderma are mediated by the upregulation of Treg cell differentiation, inhibition of Teff cell differentiation, and suppression of spleen germinal center formation. These results suggest that MET may be a potential therapeutic for scleroderma.