Acetate supplementation modulates brain histone acetylation and decreases interleukin-1β expression in a rat model of neuroinflammation

Journal of Neuroinflammation

Thad A Rosenberger¹  Heidi M Houdek¹  Mark D Smith¹  Mahmoud L Soliman¹ 

[1] Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203, USA

关键词: neuroinflammation;    histone deacetylase;    histone acetyltransferase;    histone;    cytokines;    brain;    Acetylation;   

Others  :  1212731
DOI  :  10.1186/1742-2094-9-51

 received in 2011-10-17, accepted in 2012-03-13,  发布年份 2012

【 摘 要 】

Background

Long-term acetate supplementation reduces neuroglial activation and cholinergic cell loss in a rat model of lipopolysaccharide-induced neuroinflammation. Additionally, a single dose of glyceryl triacetate, used to induce acetate supplementation, increases histone H3 and H4 acetylation and inhibits histone deacetylase activity and histone deacetylase-2 expression in normal rat brain. Here, we propose that the therapeutic effect of acetate in reducing neuroglial activation is due to a reversal of lipopolysaccharide-induced changes in histone acetylation and pro-inflammatory cytokine expression.

Methods

In this study, we examined the effect of a 28-day-dosing regimen of glyceryl triacetate, to induce acetate supplementation, on brain histone acetylation and interleukin-1β expression in a rat model of lipopolysaccharide-induced neuroinflammation. The effect was analyzed using Western blot analysis, quantitative real-time polymerase chain reaction and enzymic histone deacetylase and histone acetyltransferase assays. Statistical analysis was performed using one-way analysis of variance, parametric or nonparametric when appropriate, followed by Tukey's or Dunn's post-hoc test, respectively.

Results

We found that long-term acetate supplementation increased the proportion of brain histone H3 acetylated at lysine 9 (H3K9), histone H4 acetylated at lysine 8 and histone H4 acetylated at lysine 16. However, unlike a single dose of glyceryl triacetate, long-term treatment increased histone acetyltransferase activity and had no effect on histone deacetylase activity, with variable effects on brain histone deacetylase class I and II expression. In agreement with this hypothesis, neuroinflammation reduced the proportion of brain H3K9 acetylation by 50%, which was effectively reversed with acetate supplementation. Further, in rats subjected to lipopolysaccharide-induced neuroinflammation, the pro-inflammatory cytokine interleukin-1β protein and mRNA levels were increased by 1.3- and 10-fold, respectively, and acetate supplementation reduced this expression to control levels.

Conclusion

Based on these results, we conclude that dietary acetate supplementation attenuates neuroglial activation by effectively reducing pro-inflammatory cytokine expression by a mechanism that may involve a distinct site-specific pattern of histone acetylation and histone deacetylase expression in the brain.

【 授权许可】

   
2012 Soliman et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Cheung WL, Briggs SD, Allis CD: Acetylation and chromosomal functions. Curr Opin Cell Biol 2000, 12:326-333.
• [2]Gorisch SM, Wachsmuth M, Toth KF, Lichter P, Rippe K: Histone acetylation increases chromatin accessibility. J Cell Sci 2005, 118:5825-5834.
• [3]Strahl BD, Allis CD: The language of covalent histone modifications. Nature 2000, 403:41-45.
• [4]Shogren-Knaak M, Ishii H, Sun JM, Pazin MJ, Davie JR, Peterson CL: Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 2006, 311:844-847.
• [5]Li X, Corsa CA, Pan PW, Wu L, Ferguson D, Yu X, Min J, Dou Y: MOF and H4 K16 acetylation play important roles in DNA damage repair by modulating recruitment of DNA damage repair protein Mdc1. Mol Cell Biol 2010, 30:5335-5347.
• [6]Hezroni H, Sailaja BS, Meshorer E: Pluripotency-related, VPA-induced genome-wide H3K9 acetylation patterns in embryonic stem cells. J Biol Chem 2011, 286:35977-35988.
• [7]de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB: Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 2003, 370:737-749.
• [8]Avalos JL, Bever KM, Wolberger C: Mechanism of sirtuin inhibition by nicotinamide: altering the NAD(+) cosubstrate specificity of a Sir2 enzyme. Mol Cell 2005, 17:855-868.
• [9]Marmorstein R, Roth SY: Histone acetyltransferases: function, structure, and catalysis. Curr Opin Genet Dev 2001, 11:155-161.
• [10]Kuo MH, Brownell JE, Sobel RE, Ranalli TA, Cook RG, Edmondson DG, Roth SY, Allis CD: Transcription-linked acetylation by Gcn5p of histones H3 and H4 at specific lysines. Nature 1996, 383:269-272.
• [11]Howe L, Auston D, Grant P, John S, Cook RG, Workman JL, Pillus L: Histone H3 specific acetyltransferases are essential for cell cycle progression. Genes Dev 2001, 15:3144-3154.
• [12]Aravalli RN, Peterson PK, Lokensgard JR: Toll-like receptors in defense and damage of the central nervous system. J Neuroimmune Pharmacol 2007, 2:297-312.
• [13]Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, Vartanian T: Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci USA 2003, 100:8514-8519.
• [14]Hauss-Wegrzyniak B, Vraniak PD, Wenk GL: LPS-induced neuroinflammatory effects do not recover with time. Neuroreport 2000, 11:1759-1763.
• [15]Hauss-Wegrzyniak B, Dobrzanski P, Stoehr JD, Wenk GL: Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer's disease. Brain Res 1998, 780:294-303.
• [16]Hauss-Wegrzyniak B, Lukovic L, Bigaud M, Stoeckel ME: Brain inflammatory response induced by intracerebroventricular infusion of lipopolysaccharide: an immunohistochemical study. Brain Res 1998, 794:211-224.
• [17]Reisenauer CJ, Bhatt DP, Mitteness DJ, Slanczka ER, Gienger HM, Watt JA, Rosenberger TA: Acetate supplementation attenuates lipopolysaccharide-induced neuroinflammation. J Neurochem 2011, 117:264-274.
• [18]Rosenberger TA, Villacreses NE, Hovda JT, Bosetti F, Weerasinghe G, Wine RN, Harry GJ, Rapoport SI: Rat brain arachidonic acid metabolism is increased by a 6-day intracerebral ventricular infusion of bacterial lipopolysaccharide. J Neurochem 2004, 88:1168-1178.
• [19]Lee H, Villacreses NE, Rapoport SI, Rosenberger TA: In vivo imaging detects a transient increase in brain arachidonic acid metabolism: a potential marker of neuroinflammation. J Neurochem 2004, 91:936-945.
• [20]Mathew R, Arun P, Madhavarao CN, Moffett JR, Namboodiri MA: Progress toward acetate supplementation therapy for Canavan disease: glyceryl triacetate administration increases acetate, but not N-acetylaspartate, levels in brain. J Pharmacol Exp Ther 2005, 315:297-303.
• [21]Arun P, Madhavarao CN, Moffett JR, Hamilton K, Grunberg NE, Ariyannur PS, Gahl WA, Anikster Y, Mog S, Hallows WC, Denu JM, Namboodiri AM: Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease. J Inherit Metab Dis 2010, 33:195-210.
• [22]Arun P, Ariyannur PS, Moffett JR, Xing G, Hamilton K, Grunberg NE, Ives JA, Namboodiri AM: Metabolic acetate therapy for the treatment of traumatic brain injury. J Neurotrauma 2010, 27:293-298.
• [23]Soliman ML, Rosenberger TA: Acetate supplementation increases brain histone acetylation and inhibits histone deacetylase activity and expression. Mol Cell Biochem 2011, 352:173-180.
• [24]Adcock IM: HDAC inhibitors as anti-inflammatory agents. Br J Pharmacol 2007, 150:829-831.
• [25]Langley B, Gensert JM, Beal MF, Ratan RR: Remodeling chromatin and stress resistance in the central nervous system: histone deacetylase inhibitors as novel and broadly effective neuroprotective agents. Curr Drug Targets CNS Neurol Disord 2005, 4:41-50.
• [26]Streit WJ, Walter SA, Pennell NA: Reactive microgliosis. Prog Neurobiol 1999, 57:563-581.
• [27]Kargas G, Rudy T, Spennetta T, Takayama K, Querishi N, Shrago E: Separation and quantitation of long-chain free fatty acids in human serum by high-performance liquid chromatography. J Chromatogr 1990, 526:331-340.
• [28]Sohrabji F, Peeples KW, Marroquin OA: Local and cortical effects of olfactory bulb lesions on trophic support and cholinergic function and their modulation by estrogen. J Neurobiol 2000, 45:61-74.
• [29]Hulse RE, Kunkler PE, Fedynyshyn JP, Kraig RP: Optimization of multiplexed bead-based cytokine immunoassays for rat serum and brain tissue. J Neurosci Methods 2004, 136:87-98.
• [30]Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976, 72:248-254.
• [31]Romero-Calvo I, Ocon B, Martinez-Moya P, Suarez MD, Zarzuelo A, Martinez-Augustin O, de Medina FS: Reversible Ponceau staining as a loading control alternative to actin in western blots. Anal Biochem 2010, 401:318-320.
• [32]Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001, 25:402-408.
• [33]Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K, Iyer NG, Pérez-Rosado A, Calvo E, Lopez JA, Cano A, Calasanz MJ, Colomer D, Piris MA, Ahn N, Imhof A, Caldas C, Jenuwein T, Esteller M: Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 2005, 37:391-400.
• [34]Fraga MF, Esteller M: Towards the human cancer epigenome: a first draft of histone modifications. Cell Cycle 2005, 4:1377-1381.
• [35]Braunstein M, Sobel RE, Allis CD, Turner BM, Broach JR: Efficient transcriptional silencing in Saccharomyces cerevisiae requires a heterochromatin histone acetylation pattern. Mol Cell Biol 1996, 16:4349-4356.
• [36]Zhang B, West EJ, Van KC, Gurkoff GG, Zhou J, Zhang XM, Kozikowski AP, Lyeth BG: HDAC inhibitor increases histone H3 acetylation and reduces microglia inflammatory response following traumatic brain injury in rats. Brain Res 2008, 1226:181-191.
• [37]Kawakami K, Nakamura A, Ishigami A, Goto S, Takahashi R: Age-related difference of site-specific histone modifications in rat liver. Biogerontology 2009, 10:415-421.
• [38]Saha RN, Pahan K: HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis. Cell Death Differ 2006, 13:539-550.
• [39]Madhavarao CN, Arun P, Anikster Y, Mog SR, Staretz-Chacham O, Moffett JR, Grunberg NE, Gahl WA, Namboodiri AM: Glyceryl triacetate for Canavan disease: a low-dose trial in infants and evaluation of a higher dose for toxicity in the tremor rat model. J Inherit Metab Dis 2009, 32:640-650.
• [40]Segel R, Anikster Y, Zevin S, Steinberg A, Gahl WA, Fisher D, Staretz-Chacham O, Zimran A, Altarescu G: A safety trial of high dose glyceryl triacetate for Canavan disease. Mol Genet Metab 2011, 103:203-206.
• [41]Grossberg AJ, Zhu X, Leinninger GM, Levasseur PR, Braun TP, Myers MG Jr, Marks DL: Inflammation-induced lethargy is mediated by suppression of orexin neuron activity. J Neurosci 2011, 31:11376-11386.
• [42]Huang KF, Huang WT, Lin KC, Lin MT, Chang CP: Interleukin-1 receptor antagonist inhibits the release of glutamate, hydroxyl radicals, and prostaglandin E(2) in the hypothalamus during pyrogen-induced fever in rabbits. Eur J Pharmacol 2010, 629:125-131.
• [43]Vitkovic L, Bockaert J, Jacque C: "Inflammatory" cytokines: neuromodulators in normal brain? J Neurochem 2000, 74:457-471.
• [44]Legos JJ, Whitmore RG, Erhardt JA, Parsons AA, Tuma RF, Barone FC: Quantitative changes in interleukin proteins following focal stroke in the rat. Neurosci Lett 2000, 282:189-192.
• [45]Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White CL, Araoz C: Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci USA 1989, 86:7611-7615.
• [46]Shaftel SS, Griffin WS, O'Banion MK: The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J Neuroinflammation 2008, 5:7. BioMed Central Full Text
• [47]McGuinness MC, Powers JM, Bias WB, Schmeckpeper BJ, Segal AH, Gowda VC, Wesselingh SL, Berger J, Griffin DE, Smith KD: Human leukocyte antigens and cytokine expression in cerebral inflammatory demyelinative lesions of X-linked adrenoleukodystrophy and multiple sclerosis. J Neuroimmunol 1997, 75:174-182.
• [48]Parish CL, Finkelstein DI, Tripanichkul W, Satoskar AR, Drago J, Horne MK: The role of interleukin-1, interleukin-6, and glia in inducing growth of neuronal terminal arbors in mice. J Neurosci 2002, 22:8034-8041.
• [49]Pernot F, Heinrich C, Barbier L, Peinnequin A, Carpentier P, Dhote F, Baille V, Beaup C, Depaulis A, Dorandeu F: Inflammatory changes during epileptogenesis and spontaneous seizures in a mouse model of mesiotemporal lobe epilepsy. Epilepsia 2011, 52:2315-2325.
• [50]Meissner F, Molawi K, Zychlinsky A: Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis. Proc Natl Acad Sci USA 2010, 107:13046-13050.
• [51]Zhao ML, Kim MO, Morgello S, Lee SC: Expression of inducible nitric oxide synthase, interleukin-1 and caspase-1 in HIV-1 encephalitis. J Neuroimmunol 2001, 115:182-191.
• [52]Basu A, Krady JK, Levison SW: Interleukin-1: a master regulator of neuroinflammation. J Neurosci Res 2004, 78:151-156.
• [53]Ganter S, Northoff H, Mannel D, Gebicke-Harter PJ: Growth control of cultured microglia. J Neurosci Res 1992, 33:218-230.
• [54]Kim JH, Min KJ, Seol W, Jou I, Joe EH: Astrocytes in injury states rapidly produce anti-inflammatory factors and attenuate microglial inflammatory responses. J Neurochem 2010, 115:1161-1171.
• [55]Labow M, Shuster D, Zetterstrom M, Nunes P, Terry R, Cullinan EB, Bartfai T, Solorzano C, Moldawer LL, Chizzonite R, McIntyre KW: Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice. J Immunol 1997, 159:2452-2461.
• [56]Li Y, Liu B, Zhao H, Sailhamer EA, Fukudome EY, Zhang X, Kheirbek T, Finkelstein RA, Velmahos GC, deMoya M, Hales CA, Alam HB: Protective effect of suberoylanilide hydroxamic acid against LPS-induced septic shock in rodents. Shock 2009, 32:517-523.
• [57]Bachstetter AD, Xing B, de Almeida L, Dimayuga ER, Watterson DM, Van Eldik LJ: Microglial p38alpha MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Abeta). J Neuroinflammation 2011, 8:79. BioMed Central Full Text
• [58]Cao W, Bao C, Padalko E, Lowenstein CJ: Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling. J Exp Med 2008, 205:1491-1503.
• [59]Kim JB, Yu YM, Kim SW, Lee JK: Anti-inflammatory mechanism is involved in ethyl pyruvate-mediated efficacious neuroprotection in the postischemic brain. Brain Res 2005, 1060:188-192.
• [60]Lee JY, Kim YH, Koh JY: Protection by pyruvate against transient forebrain ischemia in rats. J Neurosci 2001, 21:RC171.
• [61]Fukushima M, Lee SM, Moro N, Hovda DA, Sutton RL: Metabolic and histologic effects of sodium pyruvate treatment in the rat after cortical contusion injury. J Neurotrauma 2009, 26:1095-1110.