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The nuclear cytokine IL-37a controls lethal cytokine storms primarily via IL-1R8-independent transcriptional upregulation of PPARγ

Cellular & Molecular Immunology volume 20, pages 1428–1444 (2023)Cite this article

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Abstract

Cytokine storms are crucial in the development of various inflammatory diseases, including sepsis and autoimmune disorders. The immunosuppressive cytokine INTERLEUKIN (IL)-37 consists of five isoforms (IL-37a-e). We identified IL-37a as a nuclear cytokine for the first time. Compared to IL-37b, IL-37a demonstrated greater efficacy in protecting against Toll-like receptor-induced cytokine hypersecretion and lethal endotoxic shock. The full-length (FL) form of IL-37a and the N-terminal fragment, which is processed by elastase, could translocate into cell nuclei through a distinctive nuclear localization sequence (NLS)/importin nuclear transport pathway. These forms exerted their regulatory effects independent of the IL-1R8 receptor by transcriptionally upregulating the nuclear receptor peroxisome proliferator-activated receptor (PPARγ). This process involved the recruitment of the H3K4 methyltransferase complex WDR5/MLL4/C/EBPβ and H3K4me1/2 to the enhancer/promoter of Pparg. The receptor-independent regulatory pathway of the nuclear IL-37a–PPARγ axis and receptor-dependent signaling by secreted IL-37a maintain homeostasis and are potential therapeutic targets for various inflammatory diseases, including sepsis.

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Acknowledgements

We thank Drs. Ruaidhri Carmody and Thomas D Otto at Glasgow University for helping with the transcriptomic microarray data analysis. This study received financial support from Versus Arthritis UK (21327 to D.X.), the National Key R&D Program of China (2021YFC2701800 and 2021YFC2701802 to Y.Z.), the National Natural Science Foundation of China (82241038, 81974248 to Y.Z. and 81900751 to X.H.), the International Joint Laboratory Program of National Children’s Medical Center (EK1125180109 to Y.Z.), the Program for Outstanding Medical Academic Leader (2019LJ19 to Y.Z.), the Shanghai Rising-Star Program (22QA1401500 to X.H.), the Shanghai Committee of Science and Technology (21140902400 to Y.Z., 23ZR1407600, 21ZR1410000 to F.J. and 20ZR1408300 to X.H.), the Shenzhen Science and Technology Peacock Team Project (KQTD20170331145453160), and the National Health Research Institutes, Taiwan, China (EM-109-PP-10).

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Author notes

  1. These authors contributed equally: Rongfei Wei, Xiao Han.

Authors and Affiliations

  1. Institute of Laboratory Animal Science, Chinese Academy of Medical Science (CAMS) and Comparative Medicine Center, Peking Union Medical College (PUMC), Beijing, China

    Rongfei Wei, Mengyuan Li, Lianfeng Zhang, Ran Gao, Jiangning Liu & Chuan Qin

  2. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biom––acromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China

    Rongfei Wei

  3. NHC Key Laboratory of Neonatal Diseases, Children’s Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China

    Xiao Han, Caiyan Zhang, Jinrong Fu & Yufeng Zhou

  4. Department of General Practice Medicine, Third Affiliated Hospital of Shenzhen University, Shenzhen, China

    Yuan Ji, Shau-Ku Huang & Damo Xu

  5. Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK

    Maria-Ioanna Christodoulou, Najwa Jameel Hameed Aga & Iain B. McInnes

  6. Tumor Immunology and Biomarkers Laboratory, Basic and Translational Cancer Research Center, Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, 2404, Cyprus

    Maria-Ioanna Christodoulou

  7. Department of Critical Care Medicine, Children’s Hospital of Fudan University, Shanghai, China

    Guoping Lu

  8. Institute of Allergy and Immunology, Health Science Center, Shenzhen University, Shenzhen, China

    Xiaojun Xiao, Xiaoyu Liu, Ping-Chang Yang & Damo Xu

  9. Department of Immunology, School of Basic Medical Science, Capital Medical University, Beijing, China

    Ying Sun

  10. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Peisong Gao & Shau-Ku Huang

  11. National Institute of Environmental Health Sciences, National Health Research Institutes, Taiwan, China

    Shau-Ku Huang

  12. State-level Regional Children’s Medical Center, Children’s Hospital of Fudan University at Xiamen (Xiamen Children’s Hospital), Fujian Provincial Key Laboratory of Neonatal Diseases, Xiamen, China

    Yufeng Zhou

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  1. Rongfei Wei
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  2. Xiao Han
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  3. Mengyuan Li
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  6. Maria-Ioanna Christodoulou
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  19. Chuan Qin
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  20. Shau-Ku Huang
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  21. Yufeng Zhou
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Contributions

D.X., R.W., and Y.Z. designed the study. R.W., X.H., M.Y., C.Z., J.F., G.L., M.I.C., X.X., X.L., and J.L. performed the experiments. L.Z. generated the four genetically modified mouse strains. M.I.C., Y.J., and M.C. performed the bioinformatics analysis. D.X., R.W., C.Q., P.Y., and Y.Z. analyzed the data. D.X., S.K.H., and Y.Z. wrote the manuscript.

Corresponding authors

Correspondence to Chuan Qin, Shau-Ku Huang, Yufeng Zhou or Damo Xu.

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The authors declare no competing interests.

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Wei, R., Han, X., Li, M. et al. The nuclear cytokine IL-37a controls lethal cytokine storms primarily via IL-1R8-independent transcriptional upregulation of PPARγ. Cell Mol Immunol 20, 1428–1444 (2023). https://doi.org/10.1038/s41423-023-01091-0

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