Metformin rescues rapamycin-induced mitochondrial dysfunction and attenuates rheumatoid arthritis with metabolic syndrome

Eun Kyung Kim,Mi-La Cho,Kyoung Ah Jung,Hong Ki Min,Seon-Yeong Lee,Jeong Won Choi,Hyun Sik Na,Da-Som Kim,Sung-Hwan Park,Jun-Geol Ryu

doi:10.1186/s13075-020-02174-3

Abstract

BackgroundRapamycin, an inhibitor of the serine/threonine protein kinase mTOR, is an immunosuppressant used to treat renal transplant recipients, but it can cause endothelial and mitochondrial dysfunction. Metformin is used for the treatment of type 2 diabetes and was reported to exert therapeutic effects against rheumatoid arthritis and obesity by improving mitochondrial dysfunction via the activation of fibroblast growth factor 21. We investigated the therapeutic effects of rapamycin–metformin combination therapy in obese mice with collagen-induced arthritis (CIA).MethodsMouse embryonic fibroblasts were treated with rapamycin, metformin, or rapamycin–metformin, and their respiratory level and mitochondrial gene expression were assayed. Mice were fed a high-fat diet, immunized with type II collagen, and subsequently treated with rapamycin–metformin daily for 10 weeks.ResultsRapamycin-treated cells exhibited dysfunction of mitochondrial respiration and decreased mitochondrial gene expression compared with rapamycin–metformin-treated cells. Moreover, rapamycin–metformin reduced the clinical arthritis score and the extent of histological inflammation and improved the metabolic profile in obese mice with CIA. Rapamycin–metformin enhanced the balance between T helper 17 and regulatory T cells in vitro and in vivo.ConclusionsThese results suggest that rapamycin–metformin is a potential therapeutic option for autoimmune arthritis.

Highlights

Rapamycin, an inhibitor of the serine/threonine protein kinase Mammalian target of rapamycin (mTOR), is an immunosuppressant used to treat renal transplant recipients, but it can cause endothelial and mitochondrial dysfunction
Rapamycin reduced T cell alloreactivity and proinflammatory cytokine levels and induced mitochondrial dysfunction, in vitro To investigate the effects of rapamycin on T cell alloreactivity, we examined its effects on CD4+ T cell proliferation in vitro
Rapamycin treatment reduced the levels of IL-17, IL-6, tumor necrosis factor-α (TNF-α), and immunoglobulin G (IgG) (IL-17: rapamycin 100 nM 458.17 ± 2.57 pg/ml vs. anti-CD3 4758.73 ± 29.58 pg/ml, IL-6: rapamycin 100 nM 199.23 ± 2.54 pg/ml vs. anti-CD3 691.22 ± 0.421 pg/ ml, TNF-α: rapamycin 100 nM 119.2 ± 4.6 pg/ml vs. anti-CD3 295.07 ± 19.55 pg/ml, IgG: rapamycin 100 nM 61.38 ± 1.56 pg/ml vs. anti-CD3 122.22 ± 0.69 pg/ml) (Fig. 1c)

Summary

Introduction

An inhibitor of the serine/threonine protein kinase mTOR, is an immunosuppressant used to treat renal transplant recipients, but it can cause endothelial and mitochondrial dysfunction. Metformin is used for the treatment of type 2 diabetes and was reported to exert therapeutic effects against rheumatoid arthritis and obesity by improving mitochondrial dysfunction via the activation of fibroblast growth factor 21. RA is treated with non-steroidal anti-inflammatory drugs, glucocorticoid, and diseasemodifying antirheumatic drugs [2] These drugs have side effects, such as bone marrow suppression, reactivation of tuberculosis, hypertension, and renal dysfunction, which hamper the long-term maintenance of therapeutic efficacy [3]. An mTOR inhibitor induced mitochondrial dysfunction, it showed therapeutic effects via suppression of osteoclastogenesis in a mouse model of RA [11]. The addition of an mTOR inhibitor to methotrexate yielded results superior to those obtained with methotrexate monotherapy with regard to the achievement of the American College of Rheumatology 20 response in patients with RA [12]

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