title: miR-17-92 cluster targets phosphatase and tensin homology and Ikaros Family Zinc Finger 4 to promote TH17-mediated inflammation.
abstract: The miR-17-92 cluster regulates a broad spectrum of biological processes of T cell immunity. This cluster was found to facilitate T cell proliferation, enhance antitumor activities and promote T cell-dependent antibody responses. However, little is known about the role of this miRNA cluster in the development of autoimmune diseases. Multiple sclerosis is a neuro-destructive autoimmune disease caused by the pathogenicity of TH17 cells, whose differentiation is tightly controlled by a variety of transcriptional and post-transcriptional regulators. Our study unveils the critical role of miR-17-92 in TH17 differentiation: T cell-specific miR-17-92 deficiency reduced TH17 differentiation and ameliorated experimental autoimmune encephalomyelitis (EAE) symptoms. We demonstrated that miR-17 and miR-19b are the two miRNAs in this cluster responsible for promoting TH17 responses. MiR-19b represses the expression of Phosphatase and Tensin Homology (PTEN), thereby augmenting the PI3K-AKT-mTOR axis essential for proper TH17 differentiation. Meanwhile, miR-17 enhances TH17 polarization by inhibiting a novel target, Ikaros Family Zinc Finger 4 (IKZF4). By establishing the miR-17-92 cluster as a key driver of TH17 responses, our data identify this miRNA cluster as a potential therapeutic target for the clinical intervention of multiple sclerosis.
authors.affiliation: From the Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Si-Qi
authors.initials: SQ
authors.lastname: Liu
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Chaoran
authors.initials: C
authors.lastname: Li
authors.forename: Baojun
authors.initials: B
authors.lastname: Zhang
authors.forename: Qi-Jing
authors.initials: QJ
authors.lastname: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005810:Multigene Family; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C575895:MIRN17-92 microRNA, mouse; C561642:MIRN19 microRNA, mouse; D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; D009419:Nerve Tissue Proteins; C118760:Zfpn1a4 protein, mouse; D051740:Ikaros Transcription Factor; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Autoimmunity; Cell Differentiation; IKZF4; Inflammation; MicroRNA; Pten; T Cell; Th17; miR-17-92