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

作　　者：Rongfei Wei Xiao Han Mengyuan Li Yuan Ji Lianfeng Zhang Maria-Ioanna Christodoulou Najwa Jameel Hameed Aga Caiyan Zhang Ran Gao Jiangning Liu Jinrong Fu Guoping Lu Xiaojun Xiao Xiaoyu Liu Ping-Chang Yang Iain B.McInnes Ying Sun Peisong Gao Chuan Qin Shau-Ku Huang Yufeng Zhou Damo Xu 

机构地区：[1]Institute of Laboratory Animal Science,Chinese Academy of Medical Science(CAMS)and Comparative Medicine Center,Peking Union Medical College(PUMC),Beijing,China [2]National Laboratory of Biomacromolecules,CAS Center for Excellence in Biom––acromolecules,Institute of Biophysics,Chinese Academy of Sciences,Beijing,100101,China [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 [4]Department of General Practice Medicine,Third Affiliated Hospital of Shenzhen University,Shenzhen,China [5]Institute of Infection,Immunity and Inflammation,University of Glasgow,Glasgow,UK [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 [7]Department of Critical Care Medicine,Children’s Hospital of Fudan University,Shanghai,China [8]Institute of Allergy and Immunology,Health Science Center,Shenzhen University,Shenzhen,China [9]Department of Immunology,School of Basic Medical Science,Capital Medical University,Beijing,China [10]Department of Medicine,Johns Hopkins University School of Medicine,Baltimore,MD,USA [11]National Institute of Environmental Health Sciences,National Health Research Institutes,Taiwan,China [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

出　　处：《Cellular & Molecular Immunology》2023年第12期1428-1444,共17页中国免疫学杂志（英文版）

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.);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).

摘　　要：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.

关 键 词：IL-37 isoforms IL-37a Nuclear cytokine receptor-independent 

分 类 号：R392[医药卫生—免疫学]