Histone deacetylase sirtuin 1 deacetylates IRF1 protein and programs dendritic cells to control Th17 protein differentiation during autoimmune inflammation.
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.
From the Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 and.
Heeyoung
H
Yang
Sang-Myeong
SM
Lee
Beixue
B
Gao
Jinping
J
Zhang
Deyu
D
Fang
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D056564:Sirtuin 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
C486767:Il27 protein, mouse; D050856:Interferon Regulatory Factor-1; D007378:Interleukins; C494258:Irf1 protein, mouse; C571327:Mog protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D016899:Interferon-beta; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
Acetylation; Autoimmune Diseases; Dendritic Cells; Epigenetics; IL-27; IRF1; Sirt1; T Cell