A T cell-specific deletion of HDAC1 protects against experimental autoimmune encephalomyelitis. (January 2018)

• Record Type: Journal Article
• Authors: Göschl, Lisa; Preglej, Teresa; Hamminger, Patricia; Bonelli, Michael; Andersen, Liisa; Boucheron, Nicole; Gülich, Alexandra F.; Müller, Lena; Saferding, Victoria; Mufazalov, Ilgiz A.; Hirahara, Kiyoshi; Seiser, Christian; Matthias, Patrick; Penz, Thomas; Schuster, Michael; Bock, Christoph; Waisman, Ari; Steiner, Günter; Ellmeier, Wilfried
• Is Part Of: Journal of autoimmunity. Volume 86(2018)
• Page Start: 51
• Page End: 61
• Publication Date: 2018-01
• Subjects: Histone deacetylases -- CD4+ T cells -- Autoimmunity -- Experimental autoimmune encephalomyelitis -- Gene targeting; BM bone marrow -- CFA complete Freund's adjuvant -- CNS central nervous system -- EAE experimental autoimmune encephalomyelitis -- HDAC histone deacetylase -- HDACi HDAC inhibitor -- MOG myelin oligodendrocyte glycoprotein -- MS multiple sclerosis -- LN lymph node -- OVA Ovalbumin -- pSTAT phospho-STAT -- RNA-seq RNA sequencing -- STAT Signal transducer and activator of transcription -- Th T helper; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2017.09.008
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: 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-cKO 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-cKO 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. Highlights: HDAC1 has a novel pathophysiological role in EAE. Mice with a T cell-specific deletion of HDAC1 are completely resistant to EAE. Selective inhibition of HDAC1 might be a promising strategy for the treatment of multiple sclerosis.