Metformin Triggers Apoptosis and Induction of the G0/G1 Switch 2 Gene in Macrophages.

Xuming Hu,Zhen Sun,Hengmi Cui,Qi Xu,Xin Zhao,Tuoyu Geng,Yi Huang,Chunfeng Dou,Liping Wang,Shihao Chen,Huan Luo,Xujing Chen,Songlei Xue

doi:10.3390/genes12091437

Xuming Hu, Zhen Sun + Show 11 more

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https://doi.org/10.3390/genes12091437

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Abstract

Metformin is a widely used antidiabetic drug for the treatment of type 2 diabetes and has been recently demonstrated to possess anti-inflammatory properties via AMPK-mediated modulation of M2 macrophage activation. However, the anti-inflammatory mechanisms of metformin on inflammatory macrophages are still not fully elucidated. In this study, we found that metformin induced apoptosis in macrophages. In particular, metformin induced apoptosis of M1 macrophages, based on M1 marker genes in apoptotic macrophages. Next, we comprehensively screened metformin-responsive genes in macrophages by RNA-seq and focused on the extrinsic apoptotic signaling pathway. The G0/G1 switch 2 gene (G0S2) was robustly up-regulated by metformin in macrophages. Overexpression of G0S2 significantly induced apoptosis of macrophages in a dose-dependent manner and blunted the function of the crucial anti-apoptotic gene Bcl-2, which was significantly reduced by metformin. These findings show that metformin promoted apoptosis of macrophages, especially M1 macrophages, via G0S2 induction and provides a novel anti-inflammatory mechanism of metformin through induction of macrophage apoptosis.

Highlights

Macrophages have a defensive function against pathogens such as microbes and play an important role in homeostatic maintenance of the body through disposal of internal waste materials and tissue repair [1,2]
The results from this study have revealed the anti-inflammatory properties of metformin by possibly inducing apoptosis of inflammatory M1 macrophages, and provide a novel anti-inflammatory mechanism of metformin on M1 macrophages via induction of apoptosis
The effects of metformin on the proliferation/viability of chicken macrophages were measured by MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) and CCK-8 (Cell Counting Kit-8) assays

Summary

Introduction

Macrophages have a defensive function against pathogens such as microbes and play an important role in homeostatic maintenance of the body through disposal of internal waste materials and tissue repair [1,2]. To perform these functions, macrophages modify their own metabolism and phenotypes. Metformin has anticancer [4,5] and pro-longevity [6,7,8] effects in addition to its antidiabetic effect. Metformin is thought to exert its primary antidiabetic action through suppression of hepatic glucose production.

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