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

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外文摘要：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(PPARy).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.

外文关键词：

IL-37 isoformsIL-37aNuclear cytokinereceptor-independent

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

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作者单位：

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

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

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

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

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

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

Department of Critical Care Medicine,Children's Hospital of Fudan University,Shanghai,China

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

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

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

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

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

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基金：

Versus Arthritis UKNational Key R&D Program of ChinaNational Key R&D Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaInternational Joint Laboratory Program of National Children's Medical CenterProgram for Outstanding Medical Academic LeaderShanghai Rising-Star ProgramShanghai Committee of Science and TechnologyShanghai Committee of Science and TechnologyShanghai Committee of Science and TechnologyShanghai Committee of Science and TechnologyShenzhen Science and Technology Peacock Team ProjectNational Health Research Institutes,Taiwan,China

项目编号：

213272021YFC27018002021YFC2701802822410388197424881900751EK11251801092019U1922QA14015002114090240023ZR140760021ZR141000020ZR1408300KQTD20170331145453160EM-109-PP-10

出版年：

2023

DOI：

10.1038/s41423-023-01091-0

中国免疫学杂志(英文版)

中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI

影响因子：0.731

ISSN：1672-7681

年,卷(期)：2023.20(12)

参考文献量77