Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes

Angiolilli C, Kabala PA, Grabiec AM, Van Baarsen IM, Ferguson BS, García S, Malvar Fernandez B, McKinsey TA, Tak PP, Fossati G, Mascagni P, Baeten DL, Reedquist KA

Ann Rheum Dis. 2017 Jan; 76(1):277-285

Speaker: Yu-Ting Lo (羅愈婷)                                     Time: 14:00-15:00, 05/24/2017

Commentator: Dr. Ai-Li Shiau (蕭璦莉 老師)            Place: Room 601

Abstract

Histone deacetylases (HDACs), the enzymes responsible for epigenetic modifications, are proposed to regulate inflammatory activation of cell populations relevant to rheumatoid arthritis (RA) and contribute to its pathogenesis The anti-inflammatory activities of HDAC inhibitors (HDACi) had been well documented and they appear to be potential therapeutic strategies for RA However, Which HDAC or combination of HDACs is specifically involved in RA pathology remains unknown. Accumulating evidence suggests that some of the class I and class IIb HDAC family members could contribute to the pathogenic mechanisms. In this study, the authors investigated the potential contribution of class I and class IIb HDACs to the inflammatory status in RA fibroblast-like synoviocytes (FLS). Herein they show that HDAC3/6i, but not HDAC1/2i and HDAC8i, significantly suppresses IL-1β-induced genes expression in RA FLS. The effect of HDAC3 silencing on the expression of HDAC3/6i target genes suggests that the HDAC3/6i prevents inflammatory gene expression primarily through its effects on HDAC3. In RA, IFN-β is an essential mediator of STAT1 activation and inhibition of this pathway prevents T cell-attracting chemokine production in FLS. The authors provide the evidence that HDAC3 controls STAT1 activity via downregulation of IFN-β expression in FLS. In conclusion, inhibition of HDAC3 in RA FLS largely recapitulates the effects of pan-HDACi in suppressing inflammatory gene expression, including type I IFN production in RA FLS. These results identify HDAC3 as a crucial epigenetic regulator of inflammation and suggest that the development of selective HDAC3 inhibitors could be beneficial in the therapy of RA and type I IFN-driven autoimmune diseases with limitation of possible side effects related to pan-HDACi.

References

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