Metformin Suppresses Systemic Autoimmunity in Roquin(san/san) Mice through Inhibiting B Cell Differentiation into Plasma Cells via Regulation of AMPK/mTOR/STAT3.

Lee SY, Moon SJ, Kim EK et al.

Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-701, South Korea.

Journal of immunology (Baltimore, Md. : 1950). Feb 2017.

Circulating autoantibodies and immune complex deposition are pathological hallmarks of systemic lupus erythematosus (SLE). B cell differentiation into plasma cells (PCs) and some T cell subsets that function as B cell helpers can be therapeutic targets of SLE. Mechanistic target of rapamycin (mTOR) signaling is implicated in the formation of B cells and germinal centers (GCs). We assessed the effect of metformin, which inhibits mTOR, on the development of autoimmunity using Roquin(san/san) mice. Oral administration of metformin inhibited the formation of splenic follicles and inflammation in kidney and liver tissues. It also decreased serum levels of anti-dsDNA Abs without affecting serum glucose levels. Moreover, metformin inhibited CD21(high)CD23(low) marginal zone B cells, B220(+)GL7(+) GC B cells, B220(-)CD138(+) PCs, and GC formation. A significant reduction in ICOS(+) follicular helper T cells was found in the spleens of the metformin-treated group compared with the vehicle-treated group. In addition, metformin inhibited Th17 cells and induced regulatory T cells. These alterations in B and T cell subsets by metformin were associated with enhanced AMPK expression and inhibition of mTOR-STAT3 signaling. Furthermore, metformin induced p53 and NF erythroid-2-related factor-2 activity in splenic CD4(+) T cells. Taken together, metformin-induced alterations in AMPK-mTOR-STAT3 signaling may have therapeutic value in SLE by inhibiting B cell differentiation into PCs and GCs.


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