c-Myc-driven glycolysis polarizes functional regulatory B cells that trigger pathogenic inflammatory responses

• Published in: Signal transduction and targeted therapy Vol. 7; no. 1; pp. 105 - 11
• Main Authors: Wang, Xu-Yan, Wei, Yuan, Hu, Bo, Liao, Yuan, Wang, Xiaodong, Wan, Wen-Hua, Huang, Chun-Xiang, Mahabati, Mahepali, Liu, Zheng-Yu, Qu, Jing-Rui, Chen, Xiao-Dan, Chen, Dong-Ping, Kuang, Dong-Ming, Wang, Xue-Hao, Chen, Yun
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 18.04.2022; Nature Publishing Group UK
• Subjects: B-Lymphocytes, Regulatory - metabolism; Biomarkers; c-Myc protein; CD38 antigen; CD4 antigen; CD69 antigen; CD8 antigen; CpG islands; Disease; Environmental factors; Genotype & phenotype; Glycolysis; Glycolysis - genetics; Humans; Immunological tolerance; Inflammation; Interleukin 10; Interleukin-10 - genetics; Laboratories; Lupus; Lupus Erythematosus, Systemic - genetics; Lymphocyte Count; Lymphocytes; Lymphocytes B; Lymphocytes T; MAP kinase; Metabolism; Myc protein; Patients; Phenotypes; Regulation; Remission (Medicine); Signal transduction; Systemic lupus erythematosus
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-022-00948-6

B cells secreting IL-10 functionally are recognized as functional regulatory B (B ) cells; however, direct evidence concerning the phenotype, regulation, and functional and clinical relevance of IL-10-secreting B cells in humans is still lacking. Here, we demonstrate that, although IL-10 itself is anti-inflammatory, IL-10 functional B cells in patients with systemic lupus erythematosus (SLE) display aggressive inflammatory features; these features shift their functions away from inducing CD8 T cell tolerance and cause them to induce a pathogenic CD4 T cell response. Functional B cells polarized by environmental factors (e.g., CPG-DNA) or directly isolated from patients with SLE mainly exhibit a CD24 CD27 CD38 CD69 phenotype that is different from that of their precursors. Mechanistically, MAPK/ERK/P38-elicited sequential oncogenic c-Myc upregulation and enhanced glycolysis are necessary for the generation and functional maintenance of functional B cells. Consistently, strategies that abrogate the activity of ERK, P38, c-Myc, and/or cell glycolysis can efficiently eliminate the pathogenic effects triggered by functional B cells.