Advertisement

Molecular Neurobiology

, Volume 54, Issue 8, pp 6391–6411 | Cite as

HDAC Inhibitor Sodium Butyrate-Mediated Epigenetic Regulation Enhances Neuroprotective Function of Microglia During Ischemic Stroke

  • Radhika Patnala
  • Thiruma V Arumugam
  • Neelima Gupta
  • S Thameem DheenEmail author
Article

Abstract

Cerebral ischemia leads to neuroinflammation and activation of microglia which further contribute to stroke pathology. Understanding regulation of microglial activation will aid in the development of therapeutic strategies that mitigate microglia-mediated neurotoxicity in neuropathologies, including ischemia. In this study, we investigated the epigenetic regulation of microglial activation by studying histone modification histone 3-lysine 9-acetylation (H3K9ac) and its regulation by histone deacetylase (HDAC) inhibitors. In vitro analysis of activated microglia showed that HDAC inhibitor, sodium butyrate (SB), alters H3K9ac enrichment and transcription at the promoters of pro-inflammatory (Tnf-α, Nos2, Stat1, Il6) and anti-inflammatory (Il10) genes while inducing the expression of genes downstream of the IL10/STAT3 anti-inflammatory pathway. In an experimental mouse (C57BL/6NTac) model of middle cerebral artery occlusion (MCAO), we observed that SB mediates neuroprotection by epigenetically regulating the microglial inflammatory response, via downregulating the expression of pro-inflammatory mediators, TNF-α and NOS2, and upregulating the expression of anti-inflammatory mediator IL10, in activated microglia. Interestingly, H3K9ac levels were found to be upregulated in activated microglia distributed in the cortex, striatum, and hippocampus of MCAO mice. A similar upregulation of H3K9ac was detected in lipopolysaccharide (LPS)-activated microglia in the Wistar rat brain, indicating that H3K9ac upregulation is consistently associated with microglial activation in vivo. Altogether, these results show evidence of HDAC inhibition being a promising molecular switch to epigenetically modify microglial behavior from pro-inflammatory to anti-inflammatory which could mitigate microglia-mediated neuroinflammation.

Keywords

Microglia H3K9ac HDAC inhibitors Ischemia Neuroinflammation Epigenetics 

Notes

Acknowledgments

This research was funded by the NUHS seed fund for basic science research (Grant No. T1-BSRG 2014-02; WBS No. R181-000-166-112).

Authors’ Contributions

RP, graduate student conceived the study, designed and performed experiments, and wrote the manuscript. TVA performed tMCAO and in vivo SB treatment. NG performed in vitro experiments relating to pSTAT3 targets and analyzed data. TVA, NG, and STD provided intellectual contribution and edited the manuscript. STD is the principal investigator of the study.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Declarations

Ethics Approval and Consent to Participate

All animal procedures were carried out in accordance with the National University of Singapore Institutional Animal Care and Use committee (IACUC) guidelines (NUS/IACUC/R15-0051). All efforts were made to minimize pain and number of animals used.

Supplementary material

12035_2016_149_MOESM1_ESM.pdf (136 kb)
Online resource 1 Table 1: Antibodies. The following table lists the antibodies used in the study and their optimal dilutions and the secondary antibody pairing respective to the experiment. Table 2: Primer sets used for qPCR gene expression analysis. Table 3: Primer sets used for CHIP-qPCR analysis (PDF 135 kb)
12035_2016_149_MOESM2_ESM.pdf (345 kb)
Online resource 2 Expression of H3K9ac, pSTAT1, and IL10 in primary microglia subject to SB treatment. a Immunofluorescence staining displayed an upregulation of H3K9ac (red) levels in primary microglia in response to SB treatment. b Immunofluorescence staining displayed an upregulation of pSTAT1 in response to LPS-mediated microglial activation in primary microglial cultures. The pSTAT1 (red) expression was suppressed in the presence of SB treatment. c Immunofluorescence staining displayed an upregulation of IL10 (red) in response to SB treatment. Primary microglial cells stained with CD11b (green) used as microglial marker. DAPI (blue) staining nuclei; n = 3. Scale bars (white) denote 20 μm. (PDF 344 kb)
12035_2016_149_MOESM3_ESM.pdf (212 kb)
Online resource 3 Enrichment of total H3 indicates nucleosome density, from cell cultures consisting of untreated control, 1 h, and 6 h LPS treatment, with and without pre-treatment with SB (2.5 mM) analyzed by chromatin immunoprecipitation assay. Primers flank promoter approx. 100 bp regions near and downstream of transcription start sites (TSS) of gene promoters Il10 (a), Fcrlb (b), Tnf-α (c), Il6 (d), Nos2 (e), and Stat1 (f), respectively. Data represented as mean + SEM; n = 3 cultures; One-way ANOVA, Tukey’s post hoc test; *p value <0.05, **<0.01; ***<0.001. (PDF 211 kb)

References

  1. 1.
    Lai SM, Alter M, Friday G, Sobel E (1994) A multifactorial analysis of risk factors for recurrence of ischemic stroke. Stroke 25(5):958–962CrossRefPubMedGoogle Scholar
  2. 2.
    Bersano A, Ballabio E, Bresolin N, Candelise L (2008) Genetic polymorphisms for the study of multifactorial stroke. Hum Mutat 29(6):776–795. doi: 10.1002/humu.20666 CrossRefPubMedGoogle Scholar
  3. 3.
    McColl B, Allan S, Rothwell N (2009) Systemic infection, inflammation and acute ischemic stroke. Neuroscience 158(3):1049–1061CrossRefPubMedGoogle Scholar
  4. 4.
    Gelderblom M, Leypoldt F, Steinbach K, Behrens D, Choe C-U, Siler DA, Arumugam TV, Orthey E et al (2009) Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 40(5):1849–1857CrossRefPubMedGoogle Scholar
  5. 5.
    Benakis C, Garcia-Bonilla L, Iadecola C, Anrather J (2014) The role of microglia and myeloid immune cells in acute cerebral ischemia. Frontiers in cellular neuroscience 8Google Scholar
  6. 6.
    Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA et al (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333(6048):1456–1458. doi: 10.1126/science.1202529 CrossRefPubMedGoogle Scholar
  7. 7.
    Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani F, Vyssotski AL, Bifone A et al (2014) Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci 17(3):400–406CrossRefPubMedGoogle Scholar
  8. 8.
    Wake H, Moorhouse AJ, Miyamoto A, Nabekura J (2013) Microglia: actively surveying and shaping neuronal circuit structure and function. Trends Neurosci 36(4):209–217CrossRefPubMedGoogle Scholar
  9. 9.
    Gomez-Nicola D, Perry VH (2015) Microglial dynamics and role in the healthy and diseased brain a paradigm of functional plasticity. Neuroscientist 21(2):169–184CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Davalos D, Grutzendler J, Yang G, Kim J, Zuo Y, Jung S, Littman D, Dustin M et al (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8(6):752–758. doi: 10.1038/nn1472 CrossRefPubMedGoogle Scholar
  11. 11.
    Dheen S, Kaur C, Ling E-A (2007) Microglial activation and its implications in the brain diseases. Curr Med Chem 14(11):1189–1197CrossRefPubMedGoogle Scholar
  12. 12.
    Morrison HW, Filosa JA (2013) A quantitative spatiotemporal analysis of microglia morphology during ischemic stroke and reperfusion. J Neuroinflammation 10(4)Google Scholar
  13. 13.
    Neumann H, Kotter M, Franklin R (2009) Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132(2):288–295CrossRefPubMedGoogle Scholar
  14. 14.
    Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, Gao Y, Chen J (2012) Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43(11):3063–3070CrossRefPubMedGoogle Scholar
  15. 15.
    Nayak D, Roth T, McGavern D (2014) Microglia development and function. Annu Rev Immunol 32:367–402. doi: 10.1146/annurev-immunol-032713-120240 CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Ransohoff R, Perry V (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145. doi: 10.1146/annurev.immunol.021908.132528 CrossRefPubMedGoogle Scholar
  17. 17.
    Christova R, Jones T, Wu P-J, Bolzer A, Costa-Pereira A, Watling D, Kerr I, Sheer D (2007) P-STAT1 mediates higher-order chromatin remodelling of the human MHC in response to IFNgamma. J Cell Sci 120(Pt 18):3262–3270. doi: 10.1242/jcs.012328 CrossRefPubMedGoogle Scholar
  18. 18.
    Przanowski P, Dabrowski M, Ellert-Miklaszewska A, Kloss M, Mieczkowski J, Kaza B, Ronowicz A, Hu F et al (2014) The signal transducers Stat1 and Stat3 and their novel target Jmjd3 drive the expression of inflammatory genes in microglia. Journal of molecular medicine (Berlin, Germany) 92(3):239–254. doi: 10.1007/s00109-013-1090-5 CrossRefGoogle Scholar
  19. 19.
    Strle K, Zhou J-H, Broussard SR, Venters HD, Johnson RW, Freund GG, Dantzer R, Kelley KW (2002) IL-10 promotes survival of microglia without activating Akt. J Neuroimmunol 122(1):9–19CrossRefPubMedGoogle Scholar
  20. 20.
    Murray PJ (2006) Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response. Curr Opin Pharmacol 6(4):379–386. doi: 10.1016/j.coph.2006.01.010 CrossRefPubMedGoogle Scholar
  21. 21.
    Shuai K, Liu B (2003) Regulation of JAK-STAT signalling in the immune system. Nature reviews. Immunology 3(11):900–911. doi: 10.1038/nri1226 PubMedGoogle Scholar
  22. 22.
    Shahbazian MD, Grunstein M (2007) Functions of site-specific histone acetylation and deacetylation. Annu Rev Biochem 76:75–100CrossRefPubMedGoogle Scholar
  23. 23.
    New M, Olzscha H, La Thangue N (2012) HDAC inhibitor-based therapies: can we interpret the code? Mol Oncol 6(6):637–656. doi: 10.1016/j.molonc.2012.09.003 CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Xuefei W, Shao L, Qiong W, Yan P, Deqin Y, Hecheng W, Dehua C, Jie Z (2013) Histone deacetylase inhibition leads to neuroprotection through regulation on glial function. Mol Neurodegener 8. doi: 10.1186/1750-1326-8-S1-P49
  25. 25.
    Dietz K, Casaccia P (2010) HDAC inhibitors and neurodegeneration: at the edge between protection and damage. Pharmacological Research: the Official Journal of the Italian Pharmacological Society 62(1):11–17. doi: 10.1016/j.phrs.2010.01.011 CrossRefGoogle Scholar
  26. 26.
    Kannan V, Brouwer N, Hanisch U-K, Regen T, Eggen B, Boddeke H (2013) Histone deacetylase inhibitors suppress immune activation in primary mouse microglia. J Neurosci Res 91(9):1133–1142. doi: 10.1002/jnr.23221 CrossRefPubMedGoogle Scholar
  27. 27.
    Davie JR (2003) Inhibition of histone deacetylase activity by butyrate. J Nutr 133(7):2485S–2493SPubMedGoogle Scholar
  28. 28.
    Kim HJ, Rowe M, Ren M, Hong J-SS, Chen P-SS, Chuang D-MM (2007) Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Exp Ther 321(3):892–901. doi: 10.1124/jpet.107.120188 CrossRefPubMedGoogle Scholar
  29. 29.
    Murphy SP, Lee RJ, McClean ME, Pemberton HE, Uo T, Morrison RS, Bastian C, Baltan S (2014) MS-275, a class I histone deacetylase inhibitor, protects the p53-deficient mouse against ischemic injury. J Neurochem 129(3):509–515. doi: 10.1111/jnc.12498 CrossRefPubMedGoogle Scholar
  30. 30.
    Fessler EB, Chibane FL, Wang Z, Chuang D-MM (2013) Potential roles of HDAC inhibitors in mitigating ischemia-induced brain damage and facilitating endogenous regeneration and recovery. Curr Pharm Des 19(28):5105–5120CrossRefPubMedGoogle Scholar
  31. 31.
    Kim HJ, Leeds P, Chuang DM (2009) The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain. J Neurochem 110(4):1226–1240. doi: 10.1111/j.1471-4159.2009.06212.x CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Lanzillotta A, Pignataro G, Branca C, Cuomo O, Sarnico I, Benarese M, Annunziato L, Spano P et al (2012) Targeted acetylation of NF-kappaB/RelA and histones by epigenetic drugs reduces post-ischemic brain injury in mice with an extended therapeutic window. Neurobiol Dis 49C:177–189. doi: 10.1016/j.nbd.2012.08.018 Google Scholar
  33. 33.
    Peterson C, Laniel M-A (2004) Histones and histone modifications. Current biology : CB 14(14):51. doi: 10.1016/j.cub.2004.07.007 CrossRefGoogle Scholar
  34. 34.
    Lok KZ, Basta M, Manzanero S, Arumugam TV (2015) Intravenous immunoglobulin (IVIg) dampens neuronal toll-like receptor-mediated responses in ischemia. J Neuroinflammation 12(1):1CrossRefGoogle Scholar
  35. 35.
    Low PC, Manzanero S, Mohannak N, Narayana VK, Nguyen TH, Kvaskoff D, Brennan FH, Ruitenberg MJ et al (2014) PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model. Nat Commun 5Google Scholar
  36. 36.
    Ferrante RJ, Kubilus JK, Lee J, Ryu H, Beesen A, Zucker B, Smith K, Kowall NW et al (2003) Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington’s disease mice. J Neurosci 23(28):9418–9427PubMedGoogle Scholar
  37. 37.
    Hu X, Zhang K, Xu C, Chen Z, Jiang H (2014) Anti-inflammatory effect of sodium butyrate preconditioning during myocardial ischemia/reperfusion. Experimental and therapeutic medicine 8(1):229–232CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    Langley B, D’Annibale MA, Suh K, Ayoub I, Tolhurst A, Bastan B, Yang L, Ko B et al (2008) Pulse inhibition of histone deacetylases induces complete resistance to oxidative death in cortical neurons without toxicity and reveals a role for cytoplasmic p21waf1/cip1 in cell cycle-independent neuroprotection. J Neurosci 28(1):163–176CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Bocchini V, Mazzolla R, Barluzzi R, Blasi E, Sick P, Kettenmann H (1992) An immortalized cell line expresses properties of activated microglial cells. J Neurosci Res 31(4):616–621CrossRefPubMedGoogle Scholar
  40. 40.
    Henn A, Lund S, Hedtjärn M, Schrattenholz A, Pörzgen P, Leist M (2009) The suitability of BV2 cells as alternative model system for primary microglia cultures or for animal experiments examining brain inflammation. ALTEX: Alternatives to animal experimentation 26(2):83–94CrossRefPubMedGoogle Scholar
  41. 41.
    Huuskonen J, Suuronen T, Nuutinen T, Kyrylenko S, Salminen A (2004) Regulation of microglial inflammatory response by sodium butyrate and short-chain fatty acids. Br J Pharmacol 141(5):874–880. doi: 10.1038/sj.bjp.0705682 CrossRefPubMedCentralPubMedGoogle Scholar
  42. 42.
    Baby N, Li Y, Ling E-A, Lu J, Dheen ST (2014) Runx1t1 (runt-related transcription factor 1; translocated to, 1) epigenetically regulates the proliferation and nitric oxide production of microglia. PLoS One 9(2):e89326CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Schindelin J, Rueden CT, Hiner MC, Eliceiri KW (2015) The ImageJ ecosystem: an open platform for biomedical image analysis. Mol Reprod Dev 82(7–8):518–529. doi: 10.1002/mrd.22489 CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C et al (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9(7):676–682CrossRefPubMedGoogle Scholar
  45. 45.
    Bolte S, Cordelieres F (2006) A guided tour into subcellular colocalization analysis in light microscopy. J Microsc 224(3):213–232CrossRefPubMedGoogle Scholar
  46. 46.
    Spandidos A, Wang X, Wang H, Seed B (2010) PrimerBank: a resource of human and mouse PCR primer pairs for gene expression detection and quantification. Nucleic Acids Res 38(suppl 1):D792–D799CrossRefPubMedGoogle Scholar
  47. 47.
    Ye J, Coulouris G, Zaretskaya I, Cutcutache I, Rozen S, Madden TL (2012) Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC bioinformatics 13(1):1CrossRefGoogle Scholar
  48. 48.
    Couper KN, Blount DG, Riley EM (2008) IL-10: the master regulator of immunity to infection. J Immunol 180(9):5771–5777CrossRefPubMedGoogle Scholar
  49. 49.
    Murray PJ (2006) STAT3-mediated anti-inflammatory signalling. Biochem Soc Trans 34(Pt 6):1028–1031CrossRefPubMedGoogle Scholar
  50. 50.
    Sleeman JE, Trinkle-Mulcahy L (2014) Nuclear bodies: new insights into assembly/dynamics and disease relevance. Curr Opin Cell Biol 28:76–83. doi: 10.1016/j.ceb.2014.03.004 CrossRefPubMedGoogle Scholar
  51. 51.
    Herrmann A, Sommer U, Pranada AL, Giese B, Küster A, Haan S, Becker W, Heinrich PC et al (2004) STAT3 is enriched in nuclear bodies. J Cell Sci 117(2):339–349. doi: 10.1242/jcs.00833 CrossRefPubMedGoogle Scholar
  52. 52.
    Hutchins AP, Poulain S, Miranda-Saavedra D (2012) Genome-wide analysis of STAT3 binding in vivo predicts effectors of the anti-inflammatory response in macrophages. Blood 119(13):e110–e119. doi: 10.1182/blood-2011-09-381483 CrossRefPubMedGoogle Scholar
  53. 53.
    Qin H, Wilson CA, Lee SJ, Benveniste EN (2006) IFN-β-induced SOCS-1 negatively regulates CD40 gene expression in macrophages and microglia. FASEB J 20(7):985–987. doi: 10.1096/fj.05-5493fje CrossRefPubMedGoogle Scholar
  54. 54.
    Koshida R, Oishi H, Hamada M, Takahashi S (2015) MafB antagonizes phenotypic alteration induced by GM-CSF in microglia. Biochemical and Biophysical Research Communications 463(1–2):109–115. doi: 10.1016/j.bbrc.2015.05.036 CrossRefPubMedGoogle Scholar
  55. 55.
    Matcovitch-Natan O, Winter DR, Giladi A, Aguilar S, Spinrad A, Sarrazin S, Ben-Yehuda H, David E et al (2016) Microglia development follows a stepwise program to regulate brain homeostasis. Science. doi: 10.1126/science.aad8670 PubMedGoogle Scholar
  56. 56.
    Zhang Y, Hoppe AD, Swanson JA (2010) Coordination of Fc receptor signaling regulates cellular commitment to phagocytosis. Proc Natl Acad Sci 107(45):19332–19337. doi: 10.1073/pnas.1008248107 CrossRefPubMedCentralPubMedGoogle Scholar
  57. 57.
    Yang TAO, Gu J, Kong BIN, Kuang Y, Cheng LIN, Cheng J, Xia XUN, Ma Y et al (2014) Gene expression profiles of patients with cerebral hematoma following spontaneous intracerebral hemorrhage. Mol Med Rep 10(4):1671–1678. doi: 10.3892/mmr.2014.2421 CrossRefPubMedCentralPubMedGoogle Scholar
  58. 58.
    Tseveleki V, Rubio R, Vamvakas S-S, White J, Taoufik E, Petit E, Quackenbush J, Probert L (2010) Comparative gene expression analysis in mouse models for multiple sclerosis, Alzheimer’s disease and stroke for identifying commonly regulated and disease-specific gene changes. Genomics 96(2):82–91. doi: 10.1016/j.ygeno.2010.04.004 CrossRefPubMedCentralPubMedGoogle Scholar
  59. 59.
    Karmodiya K, Krebs AR, Oulad-Abdelghani M, Kimura H, Tora L (2012) H3K9 and H3K14 acetylation co-occur at many gene regulatory elements, while H3K14ac marks a subset of inactive inducible promoters in mouse embryonic stem cells. BMC Genomics 13(1):424CrossRefPubMedCentralPubMedGoogle Scholar
  60. 60.
    Yarilina A, Park-Min K-H, Antoniv T, Hu X, Ivashkiv L (2008) TNF activates an IRF1-dependent autocrine loop leading to sustained expression of chemokines and STAT1-dependent type I interferon-response genes. Nat Immunol 9(4):378–387. doi: 10.1038/ni1576 CrossRefPubMedGoogle Scholar
  61. 61.
    Block M, Zecca L, Hong J-S (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8(1):57–69. doi: 10.1038/nrn2038 CrossRefPubMedGoogle Scholar
  62. 62.
    Hanisch U-K, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10(11):1387–1394. doi: 10.1038/nn1997 CrossRefPubMedGoogle Scholar
  63. 63.
    Emmanuel LG, Tal S, Jennifer M, Melanie G, Claudia J, Stoyan I, Julie H, Andrew C et al (2012) Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 13(11):1118–1128. doi: 10.1038/ni.2419 CrossRefGoogle Scholar
  64. 64.
    Lim P, Shannon M, Hardy K (2010) Epigenetic control of inducible gene expression in the immune system. Epigenomics 2(6):775–795. doi: 10.2217/epi.10.55 CrossRefPubMedGoogle Scholar
  65. 65.
    Smale ST, Natoli G (2014) Transcriptional control of inflammatory responses. Cold Spring Harb Perspect Biol 6(11):a016261CrossRefPubMedCentralPubMedGoogle Scholar
  66. 66.
    Eichhoff G, Brawek B, Garaschuk O (2011) Microglial calcium signal acts as a rapid sensor of single neuron damage in vivo. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1813(5):1014–1024. doi: 10.1016/j.bbamcr.2010.10.018 CrossRefGoogle Scholar
  67. 67.
    Dokmanovic M, Clarke C, Marks PA (2007) Histone deacetylase inhibitors: overview and perspectives. Molecular cancer research: MCR 5(10):981–989. doi: 10.1158/1541-7786.MCR-07-0324 CrossRefPubMedGoogle Scholar
  68. 68.
    Montalvo-Ortiz JL, Keegan J, Gallardo C, Gerst N, Tetsuka K, Tucker C, Matsumoto M, Fang D et al (2014) HDAC inhibitors restore the capacity of aged mice to respond to haloperidol through modulation of histone acetylation. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 39(6):1469–1478. doi: 10.1038/npp.2013.346 CrossRefGoogle Scholar
  69. 69.
    Falkenberg KJ, Johnstone RW (2014) Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov 13(9):673–691. doi: 10.1038/nrd4360 CrossRefPubMedGoogle Scholar
  70. 70.
    Faraco G, Pittelli M, Cavone L, Fossati S, Porcu M, Mascagni P, Fossati G, Moroni F et al (2009) Histone deacetylase (HDAC) inhibitors reduce the glial inflammatory response in vitro and in vivo. Neurobiol Dis 36(2):269–279. doi: 10.1016/j.nbd.2009.07.019 CrossRefPubMedGoogle Scholar
  71. 71.
    Suh H-SS, Choi S, Khattar P, Choi N, Lee SC (2010) Histone deacetylase inhibitors suppress the expression of inflammatory and innate immune response genes in human microglia and astrocytes. Journal of neuroimmune pharmacology: the official journal of the Society on NeuroImmune Pharmacology 5(4):521–532. doi: 10.1007/s11481-010-9192-0 CrossRefGoogle Scholar
  72. 72.
    Chen PS, Wang CCC, Bortner CD, Peng GSS, Wu X, Pang H, RBB L, Gean PWW et al (2007) Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience 149(1):203–212. doi: 10.1016/j.neuroscience.2007.06.053 CrossRefPubMedCentralPubMedGoogle Scholar
  73. 73.
    Kaminska B, Mota M, Pizzi M (2016) Signal transduction and epigenetic mechanisms in the control of microglia activation during neuroinflammation. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1862(3):339–351CrossRefGoogle Scholar
  74. 74.
    Xuan A, Long D, Li J, Ji W, Hong L, Zhang M, Zhang W (2012) Neuroprotective effects of valproic acid following transient global ischemia in rats. Life Sci 90(11):463–468CrossRefPubMedGoogle Scholar
  75. 75.
    Pereira L, Font-Nieves M, Van den Haute C, Baekelandt V, Planas AM, Pozas E (2015) IL-10 regulates adult neurogenesis by modulating ERK and STAT3 activity. Frontiers in cellular neuroscience 9Google Scholar
  76. 76.
    Rafehi H, Balcerczyk A, Lunke S, Kaspi A, Ziemann M, Kn H, Okabe J, Khurana I et al (2014) Vascular histone deacetylation by pharmacological HDAC inhibition. Genome Res 24(8):1271–1284. doi: 10.1101/gr.168781.113 CrossRefPubMedCentralPubMedGoogle Scholar
  77. 77.
    Sharma S, Yang B, Xi X, Grotta JC, Aronowski J, Savitz SI (2011) IL-10 directly protects cortical neurons by activating PI-3 kinase and STAT-3 pathways. Brain Res 1373:189–194CrossRefPubMedGoogle Scholar
  78. 78.
    Weber-Nordt RM, Riley JK, Greenlund AC, Moore KW, Darnell JE, Schreiber RD (1996) Stat3 recruitment by two distinct ligand-induced, tyrosine-phosphorylated docking sites in the interleukin-10 receptor intracellular domain. J Biol Chem 271(44):27954–27961CrossRefPubMedGoogle Scholar
  79. 79.
    Williams L, Bradley L, Smith A, Foxwell B (2004) Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages. J Immunol 172(1):567–576CrossRefPubMedGoogle Scholar
  80. 80.
    Sawada M, Suzumura A, Hosoya H, Marunouchi T, Nagatsu T (1999) Interleukin-10 inhibits both production of cytokines and expression of cytokine receptors in microglia. J Neurochem 72(4):1466–1471CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Radhika Patnala
    • 1
  • Thiruma V Arumugam
    • 2
  • Neelima Gupta
    • 1
  • S Thameem Dheen
    • 1
    Email author
  1. 1.Department of Anatomy, The Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
  2. 2.Department of Physiology, The Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore

Personalised recommendations