Journal
JOURNAL OF AUTOIMMUNITY
Volume 86, Issue -, Pages 51-61Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jaut.2017.09.008
Keywords
Histone deacetylases; CD4(+) T cells; Autoimmunity; Experimental autoimmune; encephalomyelitis; Gene targeting
Categories
Funding
- joint Austrian Science Fund (FWF)
- MedUni Vienna doctoral program [W1212]
- FWF projects [P23641, P26193, P29790]
- Innovative Medicines Initiative Joint Undertaking [115142]
- Deutsche Forschungsgemeinschaft (DFG) grant [CRC/TR 128]
- Austrian Science Fund (FWF) [W1212] Funding Source: Austrian Science Fund (FWF)
- Grants-in-Aid for Scientific Research [17K08876] Funding Source: KAKEN
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Multiple sclerosis (MS) is a human neurodegenerative disease characterized by the invasion of autoreactive T cells from the periphery into the CNS. Application of pan-histone deacetylase inhibitors (HDACi) ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model for MS, suggesting that HDACi might be a potential therapeutic strategy for MS. However, the function of individual HDAC members in the pathogenesis of EAE is not known. In this study we report that mice with a T cell-specific deletion of HDAC1 (using the Cd4-Cre deleter strain; HDAC1-cKO) were completely resistant to EAE despite the ability of HDAC1cKO CD4(+) T cells to differentiate into Th17 cells. RNA sequencing revealed STAT1 as a prominent upstream regulator of differentially expressed genes in activated HDAC1-cK0 CD4+ T cells and this was accompanied by a strong increase in phosphorylated STAT1 (pSTAT1). This suggests that HDAC1 controls STAT1 activity in activated CD4+ T cells. Increased pSTAT1 levels correlated with a reduced expression of the chemokine receptors Ccr4 and Ccr6, which are important for the migration of T cells into the CNS. Finally, EAE susceptibility was restored in WT:HDAC1-cK0 mixed BM chimeric mice, indicating a cell-autonomous defect. Our data demonstrate a novel pathophysiological role for HDAC1 in EAE and provide evidence that selective inhibition of HDAC1 might be a promising strategy for the treatment of MS. (C) 2017 Elsevier Ltd. All rights reserved.
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