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

Metformin attenuates bleomycin-induced scleroderma by regulating the balance of Treg/Teff cells and reducing spleen germinal center formation. Wang, Y., Zhang, S., Liang, Z., Feng, M., Zhao, X., Qin, K., Gao, C., Li, X., Guo, H., & Luo, J. Molecular Immunology, 114:72–80, October, 2019.

Paper doi abstract bibtex

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.

@article{wang_metformin_2019,
	title = {Metformin attenuates bleomycin-induced scleroderma by regulating the balance of {Treg}/{Teff} cells and reducing spleen germinal center formation},
	volume = {114},
	issn = {01615890},
	url = {https://linkinghub.elsevier.com/retrieve/pii/S0161589019300100},
	doi = {10.1016/j.molimm.2019.07.002},
	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.},
	language = {en},
	urldate = {2020-05-22},
	journal = {Molecular Immunology},
	author = {Wang, Yanlin and Zhang, Shulan and Liang, Zhaojun and Feng, Min and Zhao, Xiangcong and Qin, Kaili and Gao, Chong and Li, Xiaofeng and Guo, Hui and Luo, Jing},
	month = oct,
	year = {2019},
	pages = {72--80},
}

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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. 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