Inhibition of histone deacetylase 1 or 2 reduces microglia activation through a gene expression independent mechanism.

Abstract

Histone deacetylase (HDAC) inhibitors prevent neural cell death in in vivo models of cerebral ischaemia, brain injury and neurodegenerative disease. One mechanism by which HDAC inhibitors may do this is by suppressing the excessive inflammatory response of chronically activated microglia. However, the molecular mechanisms underlying this anti-inflammatory effect and the specific HDAC responsible are not fully understood. Recent data from in vivo rodent studies has shown that inhibition of class I HDACs suppresses neuroinflammation and is neuroprotective. In our study we have identified that selective HDAC inhibition with inhibitors apicidin, MS-275 or MI-192, or specific knockdown of HDAC1 or 2 using siRNA, suppresses the expression of cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-) in BV2 murine microglia activated with lipopolysaccharide (LPS). Furthermore, we found that in the absence of HDAC1, HDAC2 is upregulated and these increased levels are compensatory, suggesting these two HDACs have redundancy in regulating the inflammatory response of microglia. Investigating the possible underlying anti-inflammatory mechanisms suggests an increase in protein expression is not important. Taken together, this study supports the idea that inhibitors selective towards HDAC1 or HDAC2, may be therapeutically useful for targeting neuroinflammation in brain injuries and neurodegenerative disease.\n\nSignificance StatementThe number of patients suffering a stroke or a neurodegenerative disease, such as Alzheimers is increasing These conditions are severely debilitating and are leading causes of mortality, with neural cell death and loss of brain tissue being a major feature. A number of mechanisms contribute to neuronal death, including inflammation in the brain, but we still lack clinical therapies to inhibit this. The work presented here provides further insight into potential molecular therapeutic targets called histone deacetylases (HDACs), which are thought to contribute to neural cell death by promoting inflammation. We show that down regulation of HDAC1 and 2 is sufficient to reduce this inflammatory response. Our findings have clinical relevance because they identify HDAC1 and 2 as promising targets for therapy.