mTORC1‐GLUT1‐mediated glucose metabolism drives hyperactivation of B cells in primary Sjogren's syndrome

• Published in: Immunology Vol. 168; no. 3; pp. 432 - 443
• Main Authors: Luo, Xuan, Wu, Xunyao, Wang, Anqi, Chen, Yingying, Peng, Yu, Deng, Chuiwen, Zhao, Lidan, Yang, Huaxia, Zhou, Jiaxin, Peng, Linyi, Wu, Qingjun, Li, Mengtao, Zhao, Yan, Zeng, Xiaofeng, Zhang, Wen, Fei, Yunyun
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.03.2023
• Subjects: Antibodies; Autoantibodies; Autoimmune diseases; B cells; B-Lymphocytes; Cell activation; Cell proliferation; Cytosine; Glucose; Glucose metabolism; Glucose transporter; Glucose Transporter Type 1 - metabolism; Glycolysis; Humans; Immunoglobulin G; Immunoglobulin M; Lymphocytes B; Metabolic pathways; Metformin; mTORC1; Oxygen consumption; Plasma Cells; primary Sjögren's syndrome; Rapamycin; Sjogren's syndrome; Sjogren's Syndrome - metabolism; primary Sjögren's syndrome; B cells; mTORC1; glycolysis
• DOI: 10.1111/imm.13580
• ISSN: 0019-2805; 1365-2567

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. B cells from pSS patients exhibited high glycolysis capacity, maximal oxidative respiration and high GLUT1 expression. Inhibition of mTORC1 had an effect similar to that of 2‐DG. Targeting glycolysis might be a potential strategy for treating pSS patients.