mTORC1‐GLUT1‐mediated glucose metabolism drives hyperactivation of B cells in primary Sjogren's syndrome
Xuan Luo, Xunyao Wu, Anqi Wang, Yingying Chen, Yu Peng, Chuiwen Deng, Lidan Zhao, Huaxia Yang, Jiaxin Zhou, Linyi Peng, Qingjun Wu, Mengtao Li, Yan Zhao, Xiaofeng Zeng, Wen Zhang, Yunyun Fei
Abstract
Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease characterized by B cell hyperactivation and hypergrammaglobulinemia. Currently, the role of metabolic pathways in the B cells of pSS patients is poorly defined. Here, we showed that upon cytosine phosphate-guanine (CpG)/sCD40L/IL-4 stimulation, B cells proportionally increased glycolysis and oxygen consumption, and compared with B cells from healthy controls (HCs), B cells from pSS patients exhibited higher glycolysis capacity and maximal oxidative respiration (OXPHOS). We also found that glucose transporter 1 (GLUT1) expression in B cells from pSS patients was significantly higher than that in B cells from HCs. Treatment with 2-deoxy-d-glucose (2-DG) inhibited the activation of B cells in pSS patients. Both 2-DG and Metformin inhibited the proliferation, formation of plasma/plasmablasts and decreased the IgG and IgM levels in the supernatants of B cells from pSS patients. Furthermore, inhibition of mTORC1 by rapamycin had an effect similar to that of 2-DG, suppressing B cell activation, proliferation and antibody production. Taken together, we demonstrated that B cells from pSS patients are more metabolically active than those from HCs and suggested that the mTORC1-GLUT1 glycolysis pathways were the major drivers of B cell hyperactivation and autoantibody production in pSS patients.