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

• Published in: Cellular & molecular immunology 2023-12, Vol.20 (12), p.1428-1444
• Main Authors: Wei, Rongfei, Han, Xiao, Li, Mengyuan, Ji, Yuan, Zhang, Lianfeng, Christodoulou, Maria-Ioanna, Hameed Aga, Najwa Jameel, Zhang, Caiyan, Gao, Ran, Liu, Jiangning, Fu, Jinrong, Lu, Guoping, Xiao, Xiaojun, Liu, Xiaoyu, Yang, Ping-Chang, McInnes, Iain B., Sun, Ying, Gao, Peisong, Qin, Chuan, Huang, Shau-Ku, Zhou, Yufeng, Xu, Damo
• Format: Article
• Language: English
• Subjects: 631/154/555; 631/250/127/1213; 631/80/86; Antibodies; Autoimmune diseases; Biomedical and Life Sciences; Biomedicine; Cytokine Release Syndrome; Cytokine storm; Cytokines - metabolism; Elastase; Endotoxemia; Homeostasis; Humans; Immunology; Inflammatory diseases; Interleukin 1 receptors; Intracellular Signaling Peptides and Proteins - metabolism; Isoforms; Localization; Medical Microbiology; Methyltransferase; Microbiology; Nuclear transport; Peroxisome proliferator-activated receptors; PPAR gamma - metabolism; Regulatory sequences; Sepsis; Shock; Therapeutic targets; Toll-like receptors; Up-Regulation; Vaccine
• ISSN: 2042-0226; 1672-7681; 2042-0226
• DOI: 10.1038/s41423-023-01091-0

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.