Metformin Suppresses Systemic Autoimmunity in Roquinsan/san Mice through Inhibiting B Cell Differentiation into Plasma Cells via Regulation of AMPK/mTOR/STAT3
Metformin Suppresses Systemic Autoimmunity in Roquinsan/san Mice through Inhibiting B Cell Differentiation into Plasma Cells via Regulation of AMPK/mTOR/STAT3
复制标题
DOI：
10.4049/jimmunol.1403088
复制
发表时间：
2017-04-01
影响因子：
4.4
通讯作者：
Cho, Mi-La
中科院分区：
文献类型：
--
作者：
Lee, Seon-Yeong;Moon, Su-Jin;Cho, Mi-La
循环自身抗体和免疫复合物沉积是系统性红斑狼疮（SLE）的病理标志。B细胞分化为浆细胞（PCs）和一些作为B细胞辅助细胞的T细胞亚群可能是SLE的治疗靶点。雷帕霉素（mTOR）信号传导的机制靶点与B细胞和生发中心（GCs）的形成有关。我们用Roquin（san/san）小鼠评估了抑制mTOR的二甲双胍对自身免疫发展的影响。口服二甲双胍抑制脾滤泡的形成和肾、肝组织的炎症。它还降低了血清中抗dsdna抗体的水平，而不影响血清葡萄糖水平。此外，二甲双胍抑制CD21（高）CD23（低）边缘区B细胞，B220(+)GL7(+) GC B细胞，B220(-)CD138(+) PCs和GC形成。二甲双胍治疗组脾脏中ICOS+滤泡辅助性T细胞明显减少。此外，二甲双胍抑制Th17细胞并诱导调节性T细胞。二甲双胍对B细胞和T细胞亚群的改变与AMPK表达增强和mTOR-STAT3信号的抑制有关。此外，二甲双胍诱导脾脏CD4(+) T细胞中p53和NF红细胞2相关因子2的活性。综上所述，二甲双胍诱导的AMPK-mTOR-STAT3信号的改变可能通过抑制B细胞向PCs和GCs的分化而具有治疗SLE的价值。
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.