4.6 Article

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

Journal

IMMUNOLOGY
Volume 167, Issue 4, Pages 576-589

Publisher

WILEY
DOI: 10.1111/imm.13554

Keywords

extracellular signal-related kinase signalling pathway; hypoxia-inducible factor-1 alpha; interleukin-10; oxidative phosphorylation; regulatory B cells

Categories

Funding

  1. Key-Area Research and Development Program of Guangdong Province [2019B020235002, 2019B020236004]
  2. Key Scientific and Technological Program of Guangzhou City [201803040011, 201903010058, 202102020104, 202102080468]
  3. Key Scientific and Technological Projects of Guangdong Province [2015B020226002, 2016B030229002]
  4. Medical Scientific Technology Research Foundation of Guangdong Province [B2021367]
  5. National Natural Science Foundation of China [31701116, 81870511, 81900075, 82170216, 82170540]
  6. Natural Science Foundation of Guangdong Province [2015A030312013, 2021A1515010477, 2021A1515011759, 2022A1515011413, 2022A1515012452]

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This study reveals the crucial role of mitochondrial oxidative phosphorylation (OXPHOS) in regulating interleukin (IL)-10 expression in regulatory B cells (Bregs). Inhibition of OXPHOS reduces IL-10 expression in B cells and impairs the therapeutic effects of Bregs in colitis. The study also demonstrates a strong correlation between mitochondrial OXPHOS and Breg phenotype/function and suggests OXPHOS as a potential therapeutic target for autoimmune diseases.
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 mitochondria' 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-1 alpha 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.

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