Skip to main content
SpringerLink
Log in

Histone Deacetylase 2 Inhibitor CAY10683 Alleviates Lipopolysaccharide Induced Neuroinflammation Through Attenuating TLR4/NF-κB Signaling Pathway

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Neuroinflammation involves in the progression of many central nervous system diseases. Several studies have shown that histone deacetylase (HDAC) inhibitors modulated inflammatory responses in lipopolysaccharide (LPS) stimulated microglia. While, the mechanism is still unclear. The aim of present study was to investigate the effect of HDAC2 inhibitor CAY10683 on inflammatory responses and TLR4/NF-κB signaling pathways in LPS activated BV2 microglial cells and LPS induced mice neuroinflammation. The effect of CAY10683 on cell viability of BV2 microglial cells was detected by CCK-8 assay. The expressions of inflammatory cytokines were analyzed by western blotting and RT-PCR respectively. The TLR4 protein expression was measured by western blotting, immunofluorescence, immunohistochemistry respectively. The protein expressions of MYD88, phospho-NF-κB p65, NF-κB-p65, acetyl-H3 (AH3), H3, and HDAC2 were analyzed by western blotting. We found that CAY10683 could inhibit expression levels of inflammatory cytokine TNF-α and IL-1β in LPS activated BV2 microglial cells and LPS induced mice neuroinflammation. It could induce TLR4, MYD88, phospho-NF-κB p65, and HDAC2 expressions. Moreover, CAY10683 increased the acetylation of histones H3 in LPS activated BV2 microglial cells and LPS induced mice neuroinflammation. Taken together, our findings suggested that HDAC2 inhibitor CAY10683 could suppress neuroinflammatory responses and TLR4/NF-κB signaling pathways by acetylation after LPS stimulation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140(6):918–934. https://doi.org/10.1016/j.cell.2010.02.016

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Ory D, Celen S, Verbruggen A, Bormans G (2014) PET radioligands for in vivo visualization of neuroinflammation. Curr Pharm Des 20(37):5897–5913

    Article  PubMed  CAS  Google Scholar 

  3. González H, Elgueta D, Montoya A, Pacheco R (2014) Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases. J Neuroimmunol 274(1–2):1–13. https://doi.org/10.1016/j.jneuroim.2014.07.012

    Article  PubMed  CAS  Google Scholar 

  4. Lull ME, Block ML (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics 7(4):354–365. https://doi.org/10.1016/j.nurt.2010.05.014

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Garden GA, Möller T (2006) Microglia biology in health and disease. J Neuroimmune Pharmacol 1(2):127–137

    Article  PubMed  Google Scholar 

  6. Kraft AD, Harry GJ (2011) Features of microglia and neuroinflammation relevant to environmental exposure and neurotoxicity. Int J Environ Res Public Health 8(7):2980–3018. https://doi.org/10.3390/ijerph8072980

    Article  PubMed  PubMed Central  Google Scholar 

  7. Dolinoy DC, Weidman JR, Jirtle RL (2007) Epigenetic gene regulation: linking early developmental environment to adult disease. Reprod Toxicol 23(3):297–307

    Article  PubMed  CAS  Google Scholar 

  8. Jirtle RL, Skinner MK (2007) Environmental epigenomics and disease susceptibility. Nat Rev Genet 8(4):253–262

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Wade PA (2001) Transcriptional control at regulatory checkpoints by histone deacetylases: molecular connections between cancer and chromatin. Hum Mol Genet 10(7):693–698

    Article  PubMed  CAS  Google Scholar 

  10. Forsberg EC, Bresnick EH (2001) Histone acetylation beyond promoters: long-range acetylation patterns in the chromatin world. Bioessays 23(9):820–830

    Article  PubMed  CAS  Google Scholar 

  11. Kannan V, Brouwer N, Hanisch UK, Regen T, Eggen BJ, Boddeke HW (2013) Histone deacetylase inhibitors suppress immune activation in primary mouse microglia. J Neurosci Res 91(9):1133–1142. https://doi.org/10.1002/jnr.23221

    Article  PubMed  CAS  Google Scholar 

  12. 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(1):P49. https://doi.org/10.1186/1750-1326-8-S1-P49

    Article  Google Scholar 

  13. Suuronen T, Huuskonen J, Pihlaja R, Kyrylenko S, Salminen A (2003) Regulation of microglial inflammatory response by histone deacetylase inhibitors. J Neurochem 87(2):407–416

    Article  PubMed  CAS  Google Scholar 

  14. Singh V, Bhatia HS, Kumar A, de Oliveira AC, Fiebich BL (2014) Histone deacetylase inhibitors valproic acid and sodium butyrate enhance prostaglandins release in lipopolysaccharide-activated primary microglia. Neuroscience 265:147–157. https://doi.org/10.1016/j.neuroscience.2014.01.037

    Article  PubMed  CAS  Google Scholar 

  15. Kay E, Scotland RS, Whiteford JR (2014) Toll-like receptors: role in inflammation and therapeutic potential. Biofactors 40(3):284–294. https://doi.org/10.1002/biof.1156

    Article  PubMed  CAS  Google Scholar 

  16. Pardon MC (2015) Lipopolysaccharide hyporesponsiveness: protective or damaging response to the brain? Rom J Morphol Embryol 56(3):903–913

    PubMed  Google Scholar 

  17. Li J, Csakai A, Jin J, Zhang F, Yin H (2016) Therapeutic developments targeting toll-like receptor-4-mediated neuroinflammation. ChemMedChem 11(2):154–165. https://doi.org/10.1002/cmdc.201500188

    Article  PubMed  CAS  Google Scholar 

  18. Gárate I, García-Bueno B, Madrigal JL, Caso JR, Alou L, Gómez-Lus ML, Leza JC (2014) Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress. J Neuroinflamm 11:8. https://doi.org/10.1186/1742-2094-11-8

    Article  CAS  Google Scholar 

  19. Badshah H, Ali T, Kim MO (2016) Osmotin attenuates LPS-induced neuroinflammation and memory impairments via the TLR4/NFκB signaling pathway. Sci Rep 6:24493. https://doi.org/10.1038/srep24493

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Catorce MN, Gevorkian G (2016) LPS-induced murine neuroinflammation model: main features and suitability for pre-clinical assessment of nutraceuticals. Curr Neuropharmacol 14(2):155–164

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Hoogland IC, Houbolt C, van Westerloo DJ, van Gool WA, van de Beek D (2015) Systemic inflammation and microglial activation: systematic review of animal experiments. J Neuroinflamm 12:114. https://doi.org/10.1186/s12974-015-0332-6

    Article  CAS  Google Scholar 

  22. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402–408

    Article  PubMed  CAS  Google Scholar 

  23. Chen WW, Zhang X, Huang WJ (2016) Role of neuroinflammation in neurodegenerative diseases (review). Mol Med Rep 13(4):3391–3396. https://doi.org/10.3892/mmr.2016.4948

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Baufeld C, O’Loughlin E, Calcagno N, Madore C, Butovsky O (2017) Differential contribution of microglia and monocytes in neurodegenerative diseases. J Neural Transm (Vienna). https://doi.org/10.1007/s00702-017-1795-7

    Article  Google Scholar 

  25. Yuan Y, Fang M, Wu CY, Ling EA (2016) Scutellarin as a potential therapeutic agent for microglia-mediated neuroinflammation in cerebral ischemia. Neuromolecular Med 18(3):264–273. https://doi.org/10.1007/s12017-016-8394-x

    Article  PubMed  CAS  Google Scholar 

  26. Mutemberezi V, Buisseret B, Masquelier J, Guillemot-Legris O, Alhouayek M, Muccioli GG (2018) Oxysterol levels and metabolism in the course of neuroinflammation: insights from in vitro and in vivo models. J Neuroinflammation 15(1):74. https://doi.org/10.1186/s12974-018-1114-8

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wang Z, Zhang YH, Guo C, Gao HL, Zhong ML, Huang TT, Liu NN, Guo RF, Lan T, Zhang W, Wang ZY, Zhao P (2018) Tetrathiomolybdate treatment leads to the suppression of inflammatory responses through the TRAF6/NFκB pathway in LPS-stimulated BV-2 microglia. Front Aging Neurosci 10:9. https://doi.org/10.3389/fnagi.2018.00009

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hines DJ, Choi HB, Hines RM, Phillips AG, MacVicar BA (2013) Prevention of LPS-induced microglia activation, cytokine production and sickness behavior with TLR4 receptor interfering peptides. PLoS ONE 8(3):e60388. https://doi.org/10.1371/journal.pone.0060388

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Hu QP, Mao DA (2016) Histone deacetylase inhibitor SAHA attenuates post-seizure hippocampal microglia TLR4/MYD88 signaling and inhibits TLR4 gene expression via histone acetylation. BMC Neurosci 17(1):22. https://doi.org/10.1186/s12868-016-0264-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325(5942):834–840. https://doi.org/10.1126/science.1175371

    Article  PubMed  CAS  Google Scholar 

  31. Durham BS, Grigg R, Wood IC (2017) Inhibition of histone deacetylase 1 or 2 reduces induced cytokine expression in microglia through a protein synthesis independent mechanism. J Neurochem 143(2):214–224. https://doi.org/10.1111/jnc.14144

    Article  PubMed  CAS  Google Scholar 

  32. Shakespear MR, Halili MA, Irvine KM, Fairlie DP, Sweet MJ (2011) Histone deacetylases as regulators of inflammation and immunity. Trends Immunol 32(7):335–343. https://doi.org/10.1016/j.it.2011.04.001

    Article  PubMed  CAS  Google Scholar 

  33. Ashburner BP, Westerheide SD, Baldwin AS Jr (2001) The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression. Mol Cell Biol 21(20):7065–7077

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Funding

This study was supported by a grant from the National Natural Science Foundation of China (No. 81371789).

Author information

Authors and Affiliations

  1. Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Fang-Zhou Jiao, Yao Wang, Hai-Yue Zhang, Wen-bin Zhang, Lu-Wen Wang & Zuo-Jiong Gong

Authors
  1. Fang-Zhou Jiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hai-Yue Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wen-bin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lu-Wen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zuo-Jiong Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zuo-Jiong Gong.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiao, FZ., Wang, Y., Zhang, HY. et al. Histone Deacetylase 2 Inhibitor CAY10683 Alleviates Lipopolysaccharide Induced Neuroinflammation Through Attenuating TLR4/NF-κB Signaling Pathway. Neurochem Res 43, 1161–1170 (2018). https://doi.org/10.1007/s11064-018-2532-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-018-2532-9

Keywords

Search

Navigation