Abstract
BackgroundActivated T and B cells participate in the development and progression of Sjögren’s syndrome (SS). Metformin, a first-line anti-diabetic drug, exerts anti-inflammatory and immunomodulatory effects by activating AMPK. We investigated the therapeutic effect of metformin in non-obese diabetic (NOD)/ShiLtJ mice, an animal model of SS.MethodsMetformin or vehicle was administered orally to the mice for 9 weeks. The salivary flow rate was measured at 11, 13, 15, 17, and 20 weeks. Histological analysis of the salivary glands from vehicle- and metformin-treated mice was conducted. CD4+ T and B cell differentiation in the peripheral blood and/or spleen was determined by flow cytometry. Serum total IgG, IgG1, and IgG2a levels were determined by enzyme-linked immunosorbent assay.ResultsMetformin reduced salivary gland inflammation and restored the salivary flow rate. Moreover, metformin reduced the interleukin (IL)-6, tumor necrosis factor-α, IL-17 mRNA, and protein levels in the salivary glands. Metformin reduced the Th17 and Th1 cell populations and increased the regulatory T cell population in the peripheral blood and spleen and modulated the balance between Tfh and follicular regulatory T cells. In addition, metformin reduced B cell differentiation into germinal center B cells, decreased the serum immunoglobulin G level, and maintained the balance between IL-10- and IL-17-producing B cells.ConclusionMetformin suppresses effector T cells, induces regulatory T cells, and regulates B cell differentiation in an animal model of SS. In addition, metformin ameliorates salivary gland inflammation and hypofunction, suggesting that it has potential for the treatment of SS.
Highlights
Activated T and B cells participate in the development and progression of Sjögren’s syndrome (SS)
Using non-obese diabetic (NOD)/ ShiLtJ mice, an animal model of SS, we examined the effects of metformin on (1) salivary gland inflammation and salivary flow rate, (2) T cell differentiation to effector or regulatory T cells, and (3) B cell differentiation
The salivary flow rates decreased in vehicle-treated mice from weeks 11 to 20, but the salivary flow rates did not decrease in metformin-treated mice from weeks
Summary
Activated T and B cells participate in the development and progression of Sjögren’s syndrome (SS). A first-line anti-diabetic drug, exerts anti-inflammatory and immunomodulatory effects by activating AMPK. We investigated the therapeutic effect of metformin in non-obese diabetic (NOD)/ShiLtJ mice, an animal model of SS. Sjögren’s syndrome (SS) is an immune-related chronic inflammatory disease that typically involves the salivary and lacrimal glands. The pathogenesis of SS involves abnormal innate and adaptive immune responses [1]. Environmental triggers such as viral infections result in the activation of the interferon alpha pathway in the mucosal epithelial cells of individuals with certain genetic factors [2].
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