Oxidative phosphorylation regulates interleukin‐10 production in regulatory B cells via the extracellular signal‐related kinase pathway

• Published in: Immunology 2022-12, Vol.167 (4), p.576-589
• Main Authors: Zhu, Yinhong, Zhang, Xiaoran, Xie, Shujuan, Bao, Weijia, Chen, Jingrou, Wu, Qili, Lai, Xiaorong, Liu, Longshan, Xiong, Shiqiu, Peng, Yanwen
• Format: Article
• Language: English
• Subjects: Animals; Autoimmune diseases; B-Lymphocytes, Regulatory; Colitis; Cytokines; Dextran; Dextrans; extracellular signal‐related kinase signalling pathway; Fluorescence; Green fluorescent protein; hypoxia‐inducible factor‐1α; Immune system; Interleukin-10 - genetics; Interleukin-10 - metabolism; Interleukins; interleukin‐10; Kinases; Lymphocytes B; Metabolism; Mice; Mice, Inbred C57BL; Mitochondria; Molecular modelling; Oxidative Phosphorylation; Oxygen consumption; Phenotypes; Phosphorylation; regulatory B cells; Surface markers; Therapeutic targets
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.13554

Regulatory B cells (Bregs) are immune cells that constrain autoimmune response and restrict inflammation via their expression of interleukin (IL)‐10. However, the molecular mechanisms underlying Breg differentiation and IL‐10 secretion remain unclear. Previous data suggest that cellular metabolism determines both the fate and function of these cells. Here, we suggest an essential role for mitochondrial oxidative phosphorylation (OXPHOS) in the regulation of IL‐10 in these Bregs. We found that IL‐10+ B cells from IL‐10‐green fluorescent protein‐expressing mice had higher oxygen consumption rate than IL‐10− B cells. In addition, inhibition of OXPHOS decreased the expression of IL‐10 in B cells. Furthermore, suppression of OXPHOS diminished the expression of surface markers for Bregs and impaired their therapeutic effects in dextran sulphate sodium (DSS)‐induced colitis. Mechanistically, mitochondrial OXPHOS was found to regulate the transcription factor HIF‐1α through the extracellular signal‐related kinase pathway. Taken together, this study reveals a strong correlation between mitochondrial OXPHOS and Breg phenotype/function, indicating OXPHOS as a therapeutic target in autoimmune diseases driven by Breg dysfunction. Activated B cells with highly OXPHOS favors to promote IL‐10 production mainly through increasing HIF‐1α expression via regulating the phosphorylation of ERK, therefore, relieve the pathological severity of colitis in IBD mice. Pretreatment of activated B cells with oligomycin blocks OXPHOS, resulting in downregulation of ERK phosphorylation and HIF‐1α along with low IL‐10 production, thus, the therapeutic effect of activated B cells in colitis were impaired.