title: Activated microglia decrease histone acetylation and Nrf2-inducible anti-oxidant defence in astrocytes: restoring effects of inhibitors of HDACs, p38 MAPK and GSK3β.
abstract: Histone deacetylase (HDAC) inhibitors have promising neuroprotective and anti-inflammatory properties although the exact mechanisms are unclear. We have earlier showed that factors from lipopolysaccharide (LPS)-activated microglia can down-regulate the astroglial nuclear factor-erythroid 2-related factor 2 (Nrf2)-inducible anti-oxidant defence. Here we have evaluated whether histone modification and activation of GSK3β are 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 (MCM(0)) or activated with 10 ng/mL of LPS to produce MCM(10). Astrocyte-rich cultures treated with MCM(10) showed a time-dependent (0-72 h) increase in astroglial HDAC activity that correlated with lower levels of acetylation of histones H3 and H4 and decreased levels of the transcription factor Nrf2 and γ-glutamyl cysteine ligase modulatory subunit (γGCL-M) protein levels. The HDAC inhibitors valproic acid (VPA) and trichostatin-A (TSA) elevated the histone acetylation levels, restored the Nrf2-inducible anti-oxidant defence and conferred protection from oxidative stress-induced (H(2)O(2)) death in astrocyte-rich cultures exposed to MCM(10). Inhibitors of GSK3β (lithium) and p38 MAPK (SB203580) signaling pathways restored the depressed histone acetylation and Nrf2-related transcription whereas an inhibitor of Akt (Ly294002) caused a further decrease in Nrf2-related transcription. In conclusion, the study shows that well tolerated drugs such as VPA and lithium can restore an inflammatory induced depression in the Nrf2-inducible antioxidant defence, possibly via normalised histone acetylation levels.
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Sweden. Fernando.correa@medkem.gu.se
authors.forename: Fernando
authors.initials: F
authors.lastname: Correa
authors.forename: Carina
authors.initials: C
authors.lastname: Mallard
authors.forename: Michael
authors.initials: M
authors.lastname: Nilsson
authors.forename: Mats
authors.initials: M
authors.lastname: Sandberg
mesh_terms: D000107:Acetylation; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D017930:Genes, Reporter / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000975:Antioxidants; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D047428:Protein Kinase Inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D006655:Histone Deacetylases