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

ABSTRACT: B cells secreting IL-10 functionally are recognized as functional regulatory B (B_reg) cells; however, direct evidence concerning the phenotype, regulation, and functional and clinical relevance of IL-10-secreting B_reg cells in humans is still lacking. Here, we demonstrate that, although IL-10 itself is anti-inflammatory, IL-10⁺ functional B_reg 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_reg cells polarized by environmental factors (e.g., CPG-DNA) or directly isolated from patients with SLE mainly exhibit a CD24^intCD27^-CD38^-CD69^+/hi 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_reg 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_reg cells.

SUBMITTER: Wang XY

PROVIDER: S-EPMC9013717 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Wang Xu-Yan XY Wei Yuan Y Hu Bo B Liao Yuan Y Wang Xiaodong X Wan Wen-Hua WH Huang Chun-Xiang CX Mahabati Mahepali M Liu Zheng-Yu ZY Qu Jing-Rui JR Chen Xiao-Dan XD Chen Dong-Ping DP Kuang Dong-Ming DM Wang Xue-Hao XH Chen Yun Y

Signal transduction and targeted therapy 20220418 1

B cells secreting IL-10 functionally are recognized as functional regulatory B (Breg) cells; however, direct evidence concerning the phenotype, regulation, and functional and clinical relevance of IL-10-secreting Breg cells in humans is still lacking. Here, we demonstrate that, although IL-10 itself is anti-inflammatory, IL-10+ functional Breg cells in patients with systemic lupus erythematosus (SLE) display aggressive inflammatory features; these feat ...[more]

PMID: 35430810

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Project description:PurposeDeregulated Myc drives an oncogenic metabolic state, including pseudohypoxic glycolysis, adapted for the constitutive production of biomolecular precursors to feed rapid tumor cell growth. In glioblastoma, Myc facilitates renewal of the tumor-initiating cell reservoir contributing to tumor maintenance. We investigated whether targeting the Myc-driven metabolic state could be a selectively toxic therapeutic strategy for glioblastoma.Experimental designThe glycolytic dependency of Myc-driven glioblastoma was tested using (13)C metabolic flux analysis, glucose-limiting culture assays, and glycolysis inhibitors, including inhibitors of the NAD(+) salvage enzyme nicotinamide phosphoribosyl-transferase (NAMPT), in MYC and MYCN shRNA knockdown and lentivirus overexpression systems and in patient-derived glioblastoma tumorspheres with and without MYC/MYCN amplification. The in vivo efficacy of glycolyic inhibition was tested using NAMPT inhibitors in MYCN-amplified patient-derived glioblastoma orthotopic xenograft mouse models.ResultsEnforced Myc overexpression increased glucose flux and expression of glycolytic enzymes in glioblastoma cells. Myc and N-Myc knockdown and Myc overexpression systems demonstrated that Myc activity determined sensitivity and resistance to inhibition of glycolysis. Small-molecule inhibitors of glycolysis, particularly NAMPT inhibitors, were selectively toxic to MYC/MYCN-amplified patient-derived glioblastoma tumorspheres. NAMPT inhibitors were potently cytotoxic, inducing apoptosis and significantly extended the survival of mice bearing MYCN-amplified patient-derived glioblastoma orthotopic xenografts.ConclusionsMyc activation in glioblastoma generates a dependency on glycolysis and an addiction to metabolites required for glycolysis. Glycolytic inhibition via NAMPT inhibition represents a novel metabolically targeted therapeutic strategy for MYC or MYCN-amplified glioblastoma and potentially other cancers genetically driven by Myc. Clin Cancer Res; 22(17); 4452-65. ©2016 AACR.

Dataset Information

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

Publications

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

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