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 identi...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/EBPβand H3K4me1/2 to the enhancer/promoter of Pparg.The receptor-independent regulatory pathway of the nuclear IL-37a–PPARγaxis and receptor-dependent signaling by secreted IL-37a maintain homeostasis and are potential therapeutic targets for various inflammatory diseases,including sepsis.展开更多
基金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.)+5 种基金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)the National Health Research Institutes,Taiwan,China(EM-109-PP-10).
文摘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/EBPβand H3K4me1/2 to the enhancer/promoter of Pparg.The receptor-independent regulatory pathway of the nuclear IL-37a–PPARγaxis and receptor-dependent signaling by secreted IL-37a maintain homeostasis and are potential therapeutic targets for various inflammatory diseases,including sepsis.