Abstract
The type III histone deacetylase Sirt1 has recently emerged as a critical immune regulator by suppressing T cell immunity and macrophage activation during inflammation, but its role in dendritic cells (DCs) remains unknown. Here, we show that mice with genetic Sirt1 deletion specifically in DCs are resistant to MOG-induced experimental autoimmune encephalomyelitis. Loss of Sirt1 functions in DCs enhances their ability to produce IL-27 and interferon β (IFN-β). Co-cultivation of Sirt1-null DCs with CD4(+) T cells inhibited Th17 differentiation, which is reversed by anti-IL27 and anti-IFN-β neutralization antibodies. Sirt1 antagonizes acetylation of IRF1, a transcription factor that drives IL-27 production. Genetic deletion of IRF1 in Sirt1-null DCs abolishes IL-27 production and suppresses Th17 differentiation. Our results show that the histone deacetylase Sirt1 programs DCs to regulate Th17 differentiation during inflammation.
Keywords:
Acetylation; Autoimmune Diseases; Dendritic Cells; Epigenetics; IL-27; IRF1; Sirt1; T Cell.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Dendritic Cells / pathology
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Encephalomyelitis, Autoimmune, Experimental / chemically induced
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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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Encephalomyelitis, Autoimmune, Experimental / pathology
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HEK293 Cells
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Humans
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Inflammation / chemically induced
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / metabolism
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Interferon Regulatory Factor-1 / genetics
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Interferon Regulatory Factor-1 / immunology*
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Interferon Regulatory Factor-1 / metabolism
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Interferon-beta / genetics
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Interferon-beta / immunology
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Interferon-beta / metabolism
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Interleukins / genetics
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Interleukins / immunology
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Interleukins / metabolism
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Mice
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Mice, Knockout
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Myelin-Oligodendrocyte Glycoprotein / toxicity
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Sirtuin 1 / genetics
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Sirtuin 1 / immunology*
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Sirtuin 1 / metabolism
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Th17 Cells / immunology*
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Th17 Cells / metabolism
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Th17 Cells / pathology
Substances
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Il27 protein, mouse
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Interferon Regulatory Factor-1
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Interleukins
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Irf1 protein, mouse
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Mog protein, mouse
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Myelin-Oligodendrocyte Glycoprotein
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Interferon-beta
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Sirt1 protein, mouse
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Sirtuin 1