Journal
JOURNAL OF IMMUNOLOGY
Volume 198, Issue 7, Pages 2661-2670Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1403088
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Funding
- Korean Health Technology Research and Development Project [HI14C3417]
- Ministry for Health and Welfare, Republic of Korea
- Institute of Clinical Medicine Research of Bucheon St. Mary's Hospital, Research Fund [BCMC14YA11]
- National Research Foundation of Korea [NRF-2014R1A6A3A01009173]
- Korean Government
- Korea Health Promotion Institute [HI14C3417130017] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2014R1A6A3A01009173] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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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