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Vitamin B6 regulates IL-33 homeostasis to alleviate type 2 inflammation

Cellular & Molecular Immunology volume 20, pages 794–807 (2023)Cite this article

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Abstract

Interleukin-33 (IL-33) is a crucial nuclear cytokine that induces the type 2 immune response and maintains immune homeostasis. The fine-tuned regulation of IL-33 in tissue cells is critical to control of the type 2 immune response in airway inflammation, but the mechanism is still unclear. Here, we found that healthy individuals had higher phosphate-pyridoxal (PLP, an active form of vitamin B6) concentrations in the serum than asthma patients. Lower serum PLP concentrations in asthma patients were strongly associated with worse lung function and inflammation. In a mouse model of lung inflammation, we revealed that PLP alleviated the type 2 immune response and that this inhibitory effect relied on the activity of IL-33. A mechanistic study showed that in vivo, pyridoxal (PL) needed to be converted into PLP, which inhibited the type 2 response by regulating IL-33 stability. In mice heterozygous for pyridoxal kinase (PDXK), the conversion of PL to PLP was limited, and IL-33 levels were increased in the lungs, aggravating type 2 inflammation. Furthermore, we found that the mouse double minute 2 homolog (MDM2) protein, an E3 ubiquitin-protein ligase, could ubiquitinate the N-terminus of IL-33 and sustain IL-33 stability in epithelial cells. PLP reduced MDM2-mediated IL-33 polyubiquitination and decreased the level of IL-33 through the proteasome pathway. In addition, inhalation of PLP alleviated asthma-related effects in mouse models. In summary, our data indicate that vitamin B6 regulates MDM2-mediated IL-33 stability to constrain the type 2 response, which might help develop a potential preventive and therapeutic agent for allergy-related diseases.

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Acknowledgements

We are grateful to Guomei Lin for animal breeding and management. We thank Prof. Ronggui Hu and Prof. Bin Li for their suggestions to organize the manuscript. We also acknowledge the individuals who provided technical support at the Core Facility for Cell Biology and the Animal Core Facility.

Funding

This work was supported by the Ministry of Science and Technology of China (2018YFA0507402), the National Natural Science Foundation of China (32000667, 81925001, and 82170051), the Shanghai Science and Technology Innovation Action (21ZR1470600, 21JC1405800 and 20S11901800), the Key Scientific Innovation project of the Shanghai Municipal Education Commission (No. 202101070007-E00097), and the Youth Innovation Promotion Association of the Chinese Academy of Sciences (2022264).

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  1. These authors contributed equally: Songling Zhu, Shufen Zhong, Kebin Cheng, Li-Sha Zhang.

Authors and Affiliations

  1. Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230022, China

    Songling Zhu, Su Wang, Wangpeng Gu & Bing Sun

  2. State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China

    Shufen Zhong, Wen Chen, Shipeng Cheng, Liyan Ma, Zhiyang Ling, Yuying Huang, Xiaoyu Sun, Chunyan Yi, Meng Zhao, Bing Sun & Yaguang Zhang

  3. Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Institute of Respiratory Medicine, School of Medicine, Tongji University, 507 Zhengmin Road, Shanghai, 200433, China

    Kebin Cheng, Li-Sha Zhang, Jiu-wu Bai, Zu Cao, Shuo Liang & Jin-Fu Xu

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Contributions

SZhu, SZhong, KC, and LZ performed the experiments and analyzed the data. JB and ZC collected the clinical samples. WC, SC, LM, YH, and MZ provided protocols and suggestions. SW, ZL, WG, XS, and CY prepared the cell lines and reagents. SZhu, YZ, BS, JX, and SL designed the study and wrote the manuscript. YZ, BS, JX, and SL supervised the project and revised the manuscript.

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Correspondence to Shuo Liang, Jin-Fu Xu, Bing Sun or Yaguang Zhang.

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Zhu, S., Zhong, S., Cheng, K. et al. Vitamin B6 regulates IL-33 homeostasis to alleviate type 2 inflammation. Cell Mol Immunol 20, 794–807 (2023). https://doi.org/10.1038/s41423-023-01029-6

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