title: Metformin Suppresses Systemic Autoimmunity inRoquinsan/sanMice through Inhibiting B Cell Differentiation into Plasma Cells via Regulation of AMPK/mTOR/STAT3.
abstract: 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 usingRoquinsan/sanmice. 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 CD21highCD23lowmarginal 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.
authors.affiliation: Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-701, South Korea.|Immune Network, Convergent Research Consortium for Immunologic Disease, The Catholic University of Korea, Seoul 137-701, South Korea; and.
authors.forename: Seon-Yeong
authors.identifier: 0000-0003-4269-8657
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Moon
authors.affiliation: Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Kim
authors.affiliation: Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Hyeon-Beom
authors.initials: HB
authors.lastname: Seo
authors.affiliation: Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Eun-Ji
authors.initials: EJ
authors.lastname: Yang
authors.affiliation: Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Son
authors.affiliation: Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Jae-Kyung
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Jun-Ki
authors.initials: JK
authors.lastname: Min
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Sung-Hwan
authors.identifier: 0000-0003-1711-2060
authors.initials: SH
authors.lastname: Park
authors.affiliation: Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-701, South Korea; iammila@catholic.ac.kr.|Immune Network, Convergent Research Consortium for Immunologic Disease, The Catholic University of Korea, Seoul 137-701, South Korea; and.
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects / Q000276:immunology; D000818:Animals; D015551:Autoimmunity / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D002469:Cell Separation; D004195:Disease Models, Animal; D005434:Flow Cytometry; D018858:Germinal Center / Q000187:drug effects / Q000276:immunology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018613:Microscopy, Confocal; D010950:Plasma Cells / Q000187:drug effects* / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency
chemical_list: D007004:Hypoglycemic Agents; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D008687:Metformin; C501406:Rc3h1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases