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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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.
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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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DOI: https://doi.org/10.1038/s41423-023-01091-0
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