DUALISTIC SAHA DOSE-DEPENDENT EFFECTS ON GLIAL-INFLAMMATORY RESPONSE

Abstract

ABSTRACTNeuroinflammation comprises biochemical and cellular responses of the nervous system to injury, emerging as a central process in many neurological conditions. Although beneficial in nature, over-activation of the immune response may result in the production of neurotoxic factors that exacerbate the disease state. Due to the relevant role of histone acetylation in transcriptional regulation, inhibition of histone deacetylase (HDAC) activity plays a central role in the pathogenesis of inflammation. Here, we investigated the impact of HDACs inhibition in the regulation of the inflammatory response elicited by lipopolysaccharide (LPS) in glia cells using trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA). We observed that acute and prolonged exposure to low doses of TSA boosts the inflammatory response in glia cells. Conversely, TSA pre-treatment in cells exposed to LPS decreases inflammation. Additionally, we observed that low and high doses of SAHA exert opposite effects on LPS-induced inflammatory response. Low dose (100 nM) potentiates inflammatory response by increasing the production of pro-inflammatory cytokines tumour necrosis factor (TNF)-α and interleukin (IL) - 1β; and reducing the anti-inflammatory mediator IL-10. Nevertheless, 5 µM SAHA reverts the pro-towards anti-inflammatory profile.To better characterize SAHA dualistic effects in glia cells, we generated comparative genome-wide gene expression data. Simultaneous exposure to 5 µM SAHA and LPS (10 ng/ml) alters the expression of 1628 genes, while the combination of 100 nM SAHA and LPS regulates the expression of 97 transcripts. Both doses of SAHA differentially regulate important pathways involved in cellular function maintenance, homeostasis, and survival.Likewise, inhibition of the Janus Kinase - signal transducers and activators of the transcription (JAK/STAT) signalling pathway seems to mediate the anti-inflammatory effects of 5 µM SAHA. On the other hand, 100 nM SAHA increases pro-inflammatory cytokine levels possibly via modulation of the underlined feedback mechanisms triggered by IL-10 expression regulation.Together, these results contribute to outline a comprehensive picture of the involvement of HDACs inhibitors (HDACi) in the onset or prevention of neuroinflammation, showing that their effects depend on cell types, HDACi dosage and specificity, and protocol used.