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Oxidative stress-initiated one-carbon metabolism drives the generation of interleukin-10-producing B cells to resolve pneumonia

Cellular & Molecular Immunology volume 21, pages 19–32 (2024)Cite this article

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Abstract

The metabolic reprogramming underlying the generation of regulatory B cells during infectious diseases remains unknown. Using a Pseudomonas aeruginosa-induced pneumonia model, we reported that IL-10-producing B cells (IL-10+ B cells) play a key role in spontaneously resolving infection-mediated inflammation. Accumulated cytosolic reactive oxygen species (ROS) during inflammation were shown to drive IL-10+ B-cell generation by remodeling one-carbon metabolism. Depletion of the enzyme serine hydroxymethyltransferase 1 (Shmt1) led to inadequate one-carbon metabolism and decreased IL-10+ B-cell production. Furthermore, increased one-carbon flux elevated the levels of the methyl donor S-adenosylmethionine (SAM), altering histone H3 lysine 4 methylation (H3K4me) at the Il10 gene to promote chromatin accessibility and upregulate Il10 expression in B cells. Therefore, the one-carbon metabolism-associated compound ethacrynic acid (EA) was screened and found to potentially treat infectious pneumonia by boosting IL-10+ B-cell generation. Overall, these findings reveal that ROS serve as modulators to resolve inflammation by reprogramming one-carbon metabolism pathways in B cells.

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Data availability

The raw ATAC sequencing and RNA sequencing data have been submitted to the GEO repository (GSE211326, GSE211327). The untargeted metabolomic data have been submitted to the MetaboLights database with the identifier MTBLS5664. Any additional information needed to reanalyze the data reported in this paper is available from the lead contact upon request.

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Acknowledgements

This work was supported by the General Program of the National Natural Science Foundation of China (81971493, 81771736) and the Science Fund for Creative Research Groups of the National Natural Science Foundation of China (82121002). Major Program of National Natural Science Foundation of China (821300501, 82330053), Shanghai Rising-Star Program (20QA1407900), and Innovative Research Team of High-level Local Universities in Shanghai.

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  1. These authors contributed equally: Luman Wang, Yiwei Chu.

Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, Shanghai Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China

    Ying Fu, Baichao Yu, Qi Wang, Dan Zhang, Ronghua Liu, Luman Wang & Yiwei Chu

  2. Zhongshan Hospital Institute of Clinical Science, Zhongshan Hospital, Shanghai, China

    Zhou Lu

  3. Zhaotong Health Vocational College, Zhaotong, Yunnan, China

    Hushan Zhang

  4. Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China

    Feifei Luo

  5. Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China

    Ronghua Liu & Luman Wang

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  1. Ying Fu
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Contributions

YF performed the experiments, discussed and analyzed the data and wrote the paper. BY and QW performed the statistical analysis. HZ assisted in the experiment and provided reagent or technical support. DZ performed the CyTOF experiments. FL and RL discussed and wrote the paper. YC and LW conceived and supervised the study, designed the research, interpreted the results, and wrote the paper. YC is the primary contact for communication.

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Correspondence to Luman Wang or Yiwei Chu.

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Fu, Y., Yu, B., Wang, Q. et al. Oxidative stress-initiated one-carbon metabolism drives the generation of interleukin-10-producing B cells to resolve pneumonia. Cell Mol Immunol 21, 19–32 (2024). https://doi.org/10.1038/s41423-023-01109-7

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