Decreased histone acetylation and impaired Nrf2-induced anti-oxidant defence in astrocytes by activated microglia

M. SANDBERG, F. CORREA, M. NILSSON, C. MALLARD

Congreso; Neuroscience 2011 (SfN); 2011

Histone deacetylase (HDAC) inhibitors have neuroprotective and anti-inflammatory properties although the exact mechanisms are not fully clear. We have earlier (Correa et al., 2011) demonstrated that lipopolysaccharide (LPS)-activated microglia down-regulate the astroglial nuclear factor-erythroid 2-related factor 2 (Nrf2)-inducible anti-oxidant defence. Here we have evaluated whether histone modifications could be involved in these negative effects of microglia. Microglia were cultured for 24 h in serum-free culture medium to achieve microglia-conditioned medium from non-activated cells (MCM0) or activated with 10 ng/mL of LPS to produce MCM10. Astrocyte-rich cultures treated with MCM10 showed increased astroglial HDAC activity that correlated with lower levels of acetylation of histones and decreased levels of the transcription factor Nrf2 and γglutamyl cysteine ligase modulatory subunit (γGCL-M) protein levels. The HDAC inhibitors valproic acid (VPA) and trichostatin-A (TSA) increased the histone acetylation levels, restored the Nrf2-inducible anti-oxidant defence and conferred protection from oxidative stress-induced (H2O2) death in astrocyte-rich cultures exposed to MCM10. Inhibitors of GSK3beta and p38 MAPK signalling pathways restored the depressed histone acetylation and Nrf2-related transcription whereas an inhibitor of Akt caused a further decrease in Nrf2-related transcription. The study shows that inhibitors of HDACs such as VPA and TSA can restore an inflammatory induced depression in the Nrf2-inducible antioxidant defence and indicate that the Nrf2-system, at least in part, can be regulated by epigenetic mechanisms.