Abstract

Scleroderma is an autoimmune disease that causes dermal fibrosis. It occurs when collagen accumulates in tissue as a result of persistent inflammation. Th17 cells and pro-inflammatory cytokines such as IL-1β, IL-6, IL-17, and TNF-α play important roles in the pathogenesis of scleroderma. Because metformin, a medication used to treat diabetes, has effective immunoregulatory functions, we investigated its therapeutic function in scleroderma. Mice in a model of bleomycin-induced scleroderma were treated with metformin for 2 weeks. Histological assessment demonstrated protective effects of metformin against scleroderma. Metformin decreased the expression of pro-inflammatory factors in dermal tissue and lymphocytes. It also decreased mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6, IL-17, and TNF-α) and fibrosis-inducing molecules both in vivo and in vitro. These results suggest that metformin treatment has anti-inflammatory effects on lymphocytes via the inhibition of IL-17 and cytokines related to Th17 differentiation, such as IL-1β, IL-6, and TNF-α. To investigate how metformin modulates the inflammatory process in skin fibroblasts, we measured mTOR-STAT3 signaling in skin fibroblasts and found that phosphorylated mTOR and phosphorylated STAT3 protein expression were decreased by metformin treatment. These results suggest that metformin has potential to treat scleroderma by inhibiting pro-inflammatory cytokines and anti-inflammatory activity mediated by mTOR-STAT3 signaling.

Highlights

  • Scleroderma is an autoimmune disease that causes thickening of the skin, stiffness, exhaustion, and abnormal blood flow [1,2,3]

  • We demonstrated that metformin ameliorates scleroderma in a mouse model by inhibiting Th17 cells via the regulation of mammalian target of rapamycin (mTOR)-STAT3 signaling

  • H&E staining of lung and skin tissue revealed that metformin reduced lung fibrosis and skin thickness, findings we confirmed with Masson’s trichrome (MT) analyses (Fig. 1c)

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Summary

Introduction

Scleroderma is an autoimmune disease that causes thickening of the skin, stiffness, exhaustion, and abnormal blood flow [1,2,3]. The pathogenesis of scleroderma remains unclear, pro-inflammatory cytokines, the tissue microenvironment, and inflammation are contributing factors [4, 5]. T cells seem to be closely associated with the pathogenesis of scleroderma [6]. Soluble factors secreted by inflammatory cells may enhance the deposition of collagen [8]. IL-17 and Th17 cells, which are involved in autoimmune diseases such as rheumatoid arthritis [9], psoriasis [10] and lupus erythematosus [11], play a critical role in scleroderma [12,13,14]. A previous study showed that the secretion of IL-17A contributed to immune inflammation and the pathogenesis of scleroderma in an animal model [15]. Therapies that focus on inhibiting Th17 cells may be promising for treating scleroderma

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