title: The MicroRNA-183-96-182 Cluster Promotes T Helper 17 Cell Pathogenicity by Negatively Regulating Transcription Factor Foxo1 Expression.
abstract: T helper 17 (Th17) cells are key players in autoimmune diseases. However, the roles of non-coding RNAs in Th17 cell development and function are largely unknown. We found that deletion of the endoribonuclease-encoding Dicer1 specifically in Th17 cells protected mice from experimental autoimmune encephalomyelitis. We found that the Dicer1-regulated microRNA (miR)-183-96-182 cluster (miR-183C) was highly expressed in Th17 cells and was induced by cytokine IL-6-STAT3 signaling. miR-183C expression enhanced pathogenic cytokine production from Th17 cells during their development and promoted autoimmunity. Mechanistically, miR-183C in Th17 cells directly repressed expression of the transcription factor Foxo1. Foxo1 negatively regulated the pathogenicity of Th17 cells in part by inhibiting expression of cytokine receptor IL-1R1. These findings indicate that the miR-183C drives Th17 pathogenicity in autoimmune diseases via inhibition of Foxo1 and present promising therapeutic targets.
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA; Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ichiyama
authors.affiliation: Department of Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Gonzalez-Martin
authors.affiliation: Department of Immunology, MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Byung-Seok
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Department of Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Hyun Yong
authors.initials: HY
authors.lastname: Jin
authors.affiliation: Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.affiliation: Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Sabouri-Ghomi
authors.affiliation: Department of Ophthalmology, Kresge Eye Institute, Detroit, MI 48201, USA; Department of Anatomy and Cell Biology, School of Medicine, Wayne State University, Detroit, MI 48202, USA.
authors.forename: Shunbin
authors.initials: S
authors.lastname: Xu
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Pan
authors.initials: P
authors.lastname: Zheng
authors.affiliation: Department of Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: cxiao@scripps.edu.
authors.forename: Changchun
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China. Electronic address: chendong@tsinghua.edu.cn.
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D009103:Multiple Sclerosis / Q000276:immunology*; D053573:Receptors, Interleukin-1 Type I / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D058504:Th17 Cells / Q000502:physiology*
chemical_list: D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; C583355:IL1R1 protein, mouse; D015850:Interleukin-6; D035683:MicroRNAs; C540524:Mirn182 microRNA, mouse; C543802:Mirn183 microRNA, mouse; C541554:Mirn96 microRNA, mouse; D053573:Receptors, Interleukin-1 Type I; D050796:STAT3 Transcription Factor; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases