Three paralogous clusters of the miR-17-92 family of microRNAs restrain IL-12-mediated immune defense  

作　　者：Xiang Zhang Sinead MSmith Xi Wang Baohong Zhao Li Wu Xiaoyu Hu 

机构地区：[1]Institute for Immunology and School of Medicine,Tsinghua University,Beijing,100084,China [2]Tsinghua-Peking Center for Life Sciences,Beijing,10084,China [3]Beijing Key Laboratory for Immunological Research on Chronic Diseases,Beijing,100084,China [4]Department of Clinical Medicine,School of Medicine,Trinity College Dublin,Dublin,Ireland [5]Department of Immunology,Beijing Key Laboratory for Cancer Invasion and Metastasis,Advanced Innovation Center for Human Brain Protection,School of Basic Medical Sciences,Capital Medical University,Beijing,100069,China [6]Arthritis and Tissue Degeneration Program and the David Z.Rosensweig Genomics Research Center,Hospital for Special Surgery,New York,NY,10021,USA [7]Department of Medicine,Weill Cornell Medical College,New York,NY,10021,USA

出　　处：《Cellular & Molecular Immunology》2021年第7期1751-1760,共10页中国免疫学杂志（英文版）

基　　金：supported by the Ministry of Science and Technology of China National Key Research Projects(2015CB943201 to X.H.and 2015CB943200 to L.W.);National Natural Science Foundation of China grants(31821003,31725010,81571580,91642115,and 81661130161 to X.H.and 31330027 to LW.);funds from Tsinghua-Peking Center for Life Sciences(X.H.,L.W.,and XZ);funds from the Institute for Immunology at Tsinghua University(X.H.and L.W.);funds from the National Institutes of Health(BZ).

摘　　要：MicroRNAs(miRNAs)have been widely implicated in immune regulation,but evidence for the coordinated function of paralogous miRNA clusters remains scarce.Here,by using genetically modified mice with individual or combined cluster deficiencies,we found that three paralogous clusters of the miR-17-92 family of miRNAs collectively suppressed IL-12 production in macrophages.Accordingly,miR-17-92 family miRNAs deficiencies resulted in heightened production of IL-12 and thus enhanced the host defense against intracellular pathogen Listeria monocytogenes in vivo.Mechanistically,different members of the miR-17-92 family of miRNAs acted on a common target,PTEN,to inhibit IL-12 expression by modulating the PI3K-Akt-GSK3 pathway.In addition,the expression of miR-17-92 family miRNAs was collectively inhibited by the transcription factor RBP-J,and RBP-J-associated macrophage functional defects were genetically rescued by deleting three clusters of miR-17-92 family miRNAs on a RBP-J null background.Thus,our results illustrated key roles of three clusters of miR-17-92 family miRNAs in cooperatively controlling IL-12-mediated immune responses and identified miR-17-92 family miRNAs as functional targets of RBP-J in macrophages.

关 键 词：miR-17-92 family miRNAs microRNA IL-12 RBP-J MACROPHAGES 

分 类 号：R392[医药卫生—免疫学]