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.
Keywords:
Autoimmunity; Cell Differentiation; IKZF4; Inflammation; MicroRNA; Pten; T Cell; Th17; miR-17-92.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Blotting, Western
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Carrier Proteins / genetics
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Carrier Proteins / immunology
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Carrier Proteins / metabolism
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cells, Cultured
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Colitis / genetics
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Colitis / immunology
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Colitis / metabolism
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DNA-Binding Proteins
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Disease Models, Animal
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / metabolism
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Flow Cytometry
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Gene Expression Regulation / immunology
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Ikaros Transcription Factor / genetics
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Ikaros Transcription Factor / immunology*
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Ikaros Transcription Factor / metabolism
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Inflammation / genetics
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Inflammation / immunology*
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Inflammation / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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MicroRNAs / genetics
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MicroRNAs / immunology*
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MicroRNAs / metabolism
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Multigene Family
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Multiple Sclerosis / genetics
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Multiple Sclerosis / immunology
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Multiple Sclerosis / metabolism
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / immunology
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Nerve Tissue Proteins / metabolism
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / immunology*
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PTEN Phosphohydrolase / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Th17 Cells / immunology*
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Th17 Cells / metabolism
Substances
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Carrier Proteins
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DNA-Binding Proteins
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MIRN17-92 microRNA, mouse
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MIRN19 microRNA, mouse
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MicroRNAs
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Mirn17 microRNA, mouse
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Nerve Tissue Proteins
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Zfpn1a4 protein, mouse
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Ikaros Transcription Factor
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PTEN Phosphohydrolase
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Pten protein, mouse