Activated microglia decrease histone acetylation and Nrf2-inducible anti-oxidant defence in astrocytes: Restoring effects of inhibitors of HDACs, p38 MAPK and GSK3β
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 f...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2011-10-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996111002233 |
| _version_ | 1818721443973693440 |
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| author | Fernando Correa Carina Mallard Michael Nilsson Mats Sandberg |
| author_facet | Fernando Correa Carina Mallard Michael Nilsson Mats Sandberg |
| author_sort | Fernando Correa |
| collection | DOAJ |
| description | 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 (MCM0) or activated with 10 ng/mL of LPS to produce MCM10. Astrocyte-rich cultures treated with MCM10 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 (H2O2) death in astrocyte-rich cultures exposed to MCM10. 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. |
| first_indexed | 2024-12-17T20:38:49Z |
| format | Article |
| id | doaj.art-18dd598a81e54aec96d40cb014b7cd0a |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T20:38:49Z |
| publishDate | 2011-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-18dd598a81e54aec96d40cb014b7cd0a2022-12-21T21:33:21ZengElsevierNeurobiology of Disease1095-953X2011-10-01441142151Activated microglia decrease histone acetylation and Nrf2-inducible anti-oxidant defence in astrocytes: Restoring effects of inhibitors of HDACs, p38 MAPK and GSK3βFernando Correa0Carina Mallard1Michael Nilsson2Mats Sandberg3Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Sweden; Corresponding author at: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, PO BOX 420, 405 30 Göteborg, Sweden. Fax: +46 31 786 3840.Department of Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, SwedenCBR, Institute of Neuroscience and Physiology, University of Gothenburg, SwedenDepartment of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, SwedenHistone 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 (MCM0) or activated with 10 ng/mL of LPS to produce MCM10. Astrocyte-rich cultures treated with MCM10 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 (H2O2) death in astrocyte-rich cultures exposed to MCM10. 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.http://www.sciencedirect.com/science/article/pii/S0969996111002233NeuroinflammationNrf2Valproic acidTrichostatin-AEpigenetics |
| spellingShingle | Fernando Correa Carina Mallard Michael Nilsson Mats Sandberg Activated microglia decrease histone acetylation and Nrf2-inducible anti-oxidant defence in astrocytes: Restoring effects of inhibitors of HDACs, p38 MAPK and GSK3β Neurobiology of Disease Neuroinflammation Nrf2 Valproic acid Trichostatin-A Epigenetics |
| title | Activated microglia decrease histone acetylation and Nrf2-inducible anti-oxidant defence in astrocytes: Restoring effects of inhibitors of HDACs, p38 MAPK and GSK3β |
| title_full | Activated microglia decrease histone acetylation and Nrf2-inducible anti-oxidant defence in astrocytes: Restoring effects of inhibitors of HDACs, p38 MAPK and GSK3β |
| title_fullStr | Activated microglia decrease histone acetylation and Nrf2-inducible anti-oxidant defence in astrocytes: Restoring effects of inhibitors of HDACs, p38 MAPK and GSK3β |
| title_full_unstemmed | Activated microglia decrease histone acetylation and Nrf2-inducible anti-oxidant defence in astrocytes: Restoring effects of inhibitors of HDACs, p38 MAPK and GSK3β |
| title_short | Activated microglia decrease histone acetylation and Nrf2-inducible anti-oxidant defence in astrocytes: Restoring effects of inhibitors of HDACs, p38 MAPK and GSK3β |
| title_sort | activated microglia decrease histone acetylation and nrf2 inducible anti oxidant defence in astrocytes restoring effects of inhibitors of hdacs p38 mapk and gsk3β |
| topic | Neuroinflammation Nrf2 Valproic acid Trichostatin-A Epigenetics |
| url | http://www.sciencedirect.com/science/article/pii/S0969996111002233 |
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