FRI0379 Metformin Suppresses Systemic Autoimmunity in Roquinsan/San Mice Through Inhibition of B Cell Differentiation into Plasma Cells VIA AMPK/MTOR/Stat3 Pathway Regulation
Authors: S.-J. Moon, J.-K. Min
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> 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). <h3>Objectives</h3> We sought out to assess the efficacy of metformin having mTOR inhibiting property, on the development of autoimmunity using <i>Roquin</i><sup>san/san</sup> mice. <h3>Methods</h3> 20-week-old male Roquin<sup>san/san</sup> (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&amp;E staining. <h3>Results</h3> 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 CD21<sup>high</sup>CD23<sup>low</sup> marginal zone B cells, B220<sup>+</sup>GL7<sup>+</sup>GC B cells and B220<sup>-</sup>CD138<sup>+</sup> PCs occurred. Indeed, the formation of GCs were markedly decreased by metformin. The spleens of metformin-treated group demonstrated the significant reduction of ICOS<sup>+</sup> 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<sup>+</sup> T cells. <h3>Conclusions</h3> 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. <h3>References</h3> 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. 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. <h3>Acknowledgements</h3> This study was supported by a grant of the Korean Health Technology R&amp;D Project, Ministry for Health &amp; Welfare, Republic of Korea (HI14C3417). <h3>Disclosure of Interest</h3> None declared