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FRI0379 Metformin Suppresses Systemic Autoimmunity in Roquinsan/San Mice Through Inhibition of B Cell Differentiation into Plasma Cells VIA AMPK/MTOR/Stat3 Pathway Regulation
  1. S.-J. Moon,
  2. J.-K. Min
  1. Division of Rheumatology, Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Korea, Republic Of

Abstract

Background As circulating autoantibodies and immune complex deposition is a pathological hallmark of systemic lupus erythematosus (SLE), B cell differentiation into plasma cells (PCs) and some T cell subsets functioning as B-cell helpers can be therapeutic target of SLE. Mammalian target of rapamycin (mTOR) signaling is implicated in formation of B cells and germinal centers (GCs).

Objectives We sought out to assess the efficacy of metformin having mTOR inhibiting property, on the development of autoimmunity using Roquinsan/san mice.

Methods 20-week-old male Roquinsan/san (Jackson Laboratory, Bar Harbor, ME, USA) mice were used. The serum concentrations of IgG, IgG1 and dsDNA antibodies were measured using ELISA. To examine the population of B cells, the splenocytes were stained anti-B220- allophycocyanin (APC), anti-CD21-fluorescein isothiocyanate (FITC), anit-CD23-Phycoerythrin (PE), anti-CD138-PE, anti-GL7-FITC. Flow cytometry was performed using a FACSCalibur cytometer. Confocal microscopy was used to identify the subpopulations of B and T cells. Mouse spleen, liver and kidney tissues were obtained 5 weeks after the metformin treatment and were assessed using H&E staining.

Results Oral administration of metformin can inhibit the formation of splenic follicles and inflammations in kidney and liver tissues, and also decrease serum levels of anti-dsDNA antibodies, whereas not affecting serum glucose level. Metformin altered B cell subsets inhibition of CD21highCD23low marginal zone B cells, B220+GL7+GC B cells and B220-CD138+ PCs occurred. Indeed, the formation of GCs were markedly decreased by metformin. The spleens of metformin-treated group demonstrated the significant reduction of ICOS+ follicular helper T (Tfh) cells compared with those of the vehicle-treated group. Furthermore, metformin inhibited Th17 cells and reciprocally induced Treg cells. These alterations of B and T cell subsets by metformin were associated with enhanced AMPK expression and reciprocal inhibitions of mTOR-STAT3 signaling. Furthermore, metformin can induce p53 and Nrf2 activity in splenic CD4+ T cells.

Conclusions Metformin-induced alteration of AMPK-mTOR-STAT3 signaling may exert a therapeutic value on SLE via inhibiting B cells differentiation into PCs and GC formation.

References

  1. Linterman, M. A., R. J. Rigby, R. K. Wong, D. Yu, R. Brink, J. L. Cannons, P. L. Schwartzberg, M. C. Cook, G. D. Walters, and C. G. Vinuesa. 2009. Follicular helper T cells are required for systemic autoimmunity. The Journal of experimental medicine 206: 561-576.

  2. Grimaldi, C. M., D. J. Michael, and B. Diamond. 2001. Cutting Edge: Expansion and Activation of A Population of Autoreactive Marginal Zone B Cells in a Model of Estrogen-Induced Lupus. The Journal of Immunology 167: 1886-1890.

Acknowledgements This study was supported by a grant of the Korean Health Technology R&D Project, Ministry for Health & Welfare, Republic of Korea (HI14C3417).

Disclosure of Interest None declared

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