Journal
ARTHRITIS RESEARCH & THERAPY
Volume 21, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13075-019-1904-0
Keywords
Metformin; Sjogren's syndrome; AMP-activated protein kinase; TOR serine-threonine kinase; STAT3; Th17 cells; B-lymphocyte
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Funding
- Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea [HI13C0016]
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Background: Activated T and B cells participate in the development and progression of Sjogren'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. Methods: Metformin 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. Results: Metformin reduced salivary gland inflammation and restored the salivary flow rate. Moreover, metformin reduced the interleukin (IL)-6, tumor necrosis factor-alpha, 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. Conclusion: Metformin 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.
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