Generic placeholder image

Current Molecular Pharmacology

Author(s): Mitsuaki Moriyama*, Yasunori Nishimura, Ryosuke Kurebayashi, Tomoki Minamihata, Kenji Kawabe, Katsura Takano and Yoichi Nakamura

DOI: 10.2174/1874467213666200420101048

DownloadDownload PDF Flyer Cite As
Acetate Suppresses Lipopolysaccharide-stimulated Nitric Oxide Production in Primary Rat Microglia but not in BV-2 Microglia Cells

Page: [253 - 260] Pages: 8

  • * (Excluding Mailing and Handling)

Explore Articles
About Journal
For Authors
For Editors
For Reviewers

Abstract

Aims: To show that acetate attenuates neuroinflammatory responses in activated microglia. Background: Dietary acetate supplementation alleviates neuroglial activation in a rat model of neuroinflammation induced by intraventricular administration of lipopolysaccharide (LPS). However, the precise mechanism(s) underlying the anti-inflammatory effect of acetate, is not fully understood.

Objective: To determine whether acetate has inhibitory effects on LPS-induced neuroinflammatory responses in microglia.

Methods: We examined LPS-stimulated nitric oxide (NO) production in primary rat microglia and BV-2 cells. Protein expression of inducible NO synthase (iNOS) was determined by western blot analysis. The intracellular generation of reactive oxygen species (ROS) and glutathione (GSH) were also evaluated.

Results: In primary microglia, acetate decreased LPS-stimulated NO production in a dose-dependent manner, reaching significance at greater than 10 mM, and cell viability was not affected. Acetate suppressed LPS-induced expression of iNOS protein concomitantly with the decrease in NO. The LPS-induced increase in intracellular ROS production was attenuated by acetate. In addition, acetate prevented LPS-induced reduction of GSH. Notably, such suppressive effects of acetate on NO and ROS production were not observed in BV-2 cells.

Conclusion: These findings suggest that acetate may alleviate neuroinflammatory responses by attenuating NO and ROS production in primary microglia but not in BV-2 cells.

Other: All animals received humane care, and the animal protocols used in this study were approved by the Ethics Committees for Animal Experimentation.

Keywords: Acetate, microglia, neuroinflammation, nitric oxide, BV-2 cell line.

Graphical Abstract

[1]
Kreutzberg, G.W. Microglia: a sensor for pathological events in the CNS. Trends Neurosci., 1996, 19(8), 312-318.
[http://dx.doi.org/10.1016/0166-2236(96)10049-7] [PMID: 8843599]
[2]
Block, M.L.; Zecca, L.; Hong, J.S. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci., 2007, 8(1), 57-69.
[http://dx.doi.org/10.1038/nrn2038] [PMID: 17180163]
[3]
Tan, J.; McKenzie, C.; Potamitis, M.; Thorburn, A.N.; Mackay, C.R.; Macia, L. The role of short-chain fatty acids in health and disease. Adv. Immunol., 2014, 121, 91-119.
[http://dx.doi.org/10.1016/B978-0-12-800100-4.00003-9] [PMID: 24388214]
[4]
Vinolo, M.A.; Rodrigues, H.G.; Nachbar, R.T.; Curi, R. Regulation of inflammation by short chain fatty acids. Nutrients, 2011, 3(10), 858-876.
[http://dx.doi.org/10.3390/nu3100858] [PMID: 22254083]
[5]
Sivaprakasam, S.; Prasad, P.D.; Singh, N. Benefits of short-chain fatty acids and their receptors in inflammation and carcinogenesis. Pharmacol. Ther., 2016, 164, 144-151.
[http://dx.doi.org/10.1016/j.pharmthera.2016.04.007] [PMID: 27113407]
[6]
Okabe, S.; Kodama, Y.; Cao, H.; Johannessen, H.; Zhao, C.M.; Wang, T.C.; Takahashi, R.; Chen, D. Topical application of acetic acid in cytoreduction of gastric cancer. A technical report using mouse model. J. Gastroenterol. Hepatol., 2012, 27(Suppl. 3), 40-48.
[http://dx.doi.org/10.1111/j.1440-1746.2012.07070.x] [PMID: 22486870]
[7]
van der Beek, C.M.; Dejong, C.H.C.; Troost, F.J.; Masclee, A.A.M.; Lenaerts, K. Role of short-chain fatty acids in colonic inflammation, carcinogenesis, and mucosal protection and healing. Nutr. Rev., 2017, 75(4), 286-305.
[http://dx.doi.org/10.1093/nutrit/nuw067] [PMID: 28402523]
[8]
Chen, J.S.; Faller, D.V.; Spanjaard, R.A. Short-chain fatty acid inhibitors of histone deacetylases: promising anticancer therapeutics? Curr. Cancer Drug Targets, 2003, 3(3), 219-236.
[http://dx.doi.org/10.2174/1568009033481994] [PMID: 12769690]
[9]
Alvarez-Curto, E.; Milligan, G. Metabolism meets immunity: The role of free fatty acid receptors in the immune system. Biochem. Pharmacol., 2016, 114, 3-13.
[http://dx.doi.org/10.1016/j.bcp.2016.03.017] [PMID: 27002183]
[10]
Schönfeld, P.; Wojtczak, L. Short- and medium-chain fatty acids in energy metabolism: the cellular perspective. J. Lipid Res., 2016, 57(6), 943-954.
[http://dx.doi.org/10.1194/jlr.R067629] [PMID: 27080715]
[11]
Shimazu, T.; Hirschey, M.D.; Huang, J.Y.; Ho, L.T.; Verdin, E. Acetate metabolism and aging: An emerging connection. Mech. Ageing Dev., 2010, 131(7-8), 511-516.
[http://dx.doi.org/10.1016/j.mad.2010.05.001] [PMID: 20478325]
[12]
Deelchand, D.K.; Shestov, A.A.; Koski, D.M.; Uğurbil, K.; Henry, P.G. Acetate transport and utilization in the rat brain. J. Neurochem., 2009, 109(Suppl. 1), 46-54.
[http://dx.doi.org/10.1111/j.1471-4159.2009.05895.x] [PMID: 19393008]
[13]
Frost, G.; Sleeth, M.L.; Sahuri-Arisoylu, M.; Lizarbe, B.; Cerdan, S.; Brody, L.; Anastasovska, J.; Ghourab, S.; Hankir, M.; Zhang, S.; Carling, D.; Swann, J.R.; Gibson, G.; Viardot, A.; Morrison, D.; Louise Thomas, E.; Bell, J.D. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat. Commun., 2014, 5, 3611.
[http://dx.doi.org/10.1038/ncomms4611] [PMID: 24781306]
[14]
St Laurent, R.; O’Brien, L.M.; Ahmad, S.T. Sodium butyrate improves locomotor impairment and early mortality in a rotenone-induced Drosophila model of Parkinson’s disease. Neuroscience, 2013, 246, 382-390.
[http://dx.doi.org/10.1016/j.neuroscience.2013.04.037] [PMID: 23623990]
[15]
Govindarajan, N.; Agis-Balboa, R.C.; Walter, J.; Sananbenesi, F.; Fischer, A. Sodium butyrate improves memory function in an Alzheimer’s disease mouse model when administered at an advanced stage of disease progression. J. Alzheimers Dis., 2011, 26(1), 187-197.
[http://dx.doi.org/10.3233/JAD-2011-110080] [PMID: 21593570]
[16]
Reisenauer, C.J.; Bhatt, D.P.; Mitteness, D.J.; Slanczka, E.R.; Gienger, H.M.; Watt, J.A.; Rosenberger, T.A. Acetate supplementation attenuates lipopolysaccharide-induced neuroinflammation. J. Neurochem., 2011, 117(2), 264-274.
[http://dx.doi.org/10.1111/j.1471-4159.2011.07198.x] [PMID: 21272004]
[17]
Moriyama, M.; Kurebayashi, R.; Kawabe, K.; Takano, K.; Nakamura, Y. Acetate attenuates lipopolysaccharide-induced nitric oxide production through an anti-oxidative mechanism in cultured primary rat astrocytes. Neurochem. Res., 2016, 41(11), 3138-3146.
[http://dx.doi.org/10.1007/s11064-016-2038-2] [PMID: 27542961]
[18]
Sochocka, M.; Diniz, B.S.; Leszek, J. Inflammatory Response in the CNS: Friend or Foe? Mol. Neurobiol., 2017, 54(10), 8071-8089.
[http://dx.doi.org/10.1007/s12035-016-0297-1] [PMID: 27889895]
[19]
Block, M.L.; Hong, J.S. Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog. Neurobiol., 2005, 76(2), 77-98.
[http://dx.doi.org/10.1016/j.pneurobio.2005.06.004] [PMID: 16081203]
[20]
Czirr, E.; Wyss-Coray, T. The immunology of neurodegeneration. J. Clin. Invest., 2012, 122(4), 1156-1163.
[http://dx.doi.org/10.1172/JCI58656] [PMID: 22466657]
[21]
Olson, J.K.; Miller, S.D. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J. Immunol., 2004, 173(6), 3916-3924.
[http://dx.doi.org/10.4049/jimmunol.173.6.3916] [PMID: 15356140]
[22]
Blasi, E.; Barluzzi, R.; Bocchini, V.; Mazzolla, R.; Bistoni, F. Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J. Neuroimmunol., 1990, 27(2-3), 229-237.
[http://dx.doi.org/10.1016/0165-5728(90)90073-V] [PMID: 2110186]
[23]
Horvath, R.J.; Nutile-McMenemy, N.; Alkaitis, M.S.; Deleo, J.A. Differential migration, LPS-induced cytokine, chemokine, and NO expression in immortalized BV-2 and HAPI cell lines and primary microglial cultures. J. Neurochem., 2008, 107(2), 557-569.
[http://dx.doi.org/10.1111/j.1471-4159.2008.05633.x] [PMID: 18717813]
[24]
de Jong, E.K.; de Haas, A.H.; Brouwer, N.; van Weering, H.R.; Hensens, M.; Bechmann, I.; Pratley, P.; Wesseling, E.; Boddeke, H.W.; Biber, K. Expression of CXCL4 in microglia in vitro and in vivo and its possible signaling through CXCR3. J. Neurochem., 2008, 105(5), 1726-1736.
[http://dx.doi.org/10.1111/j.1471-4159.2008.05267.x] [PMID: 18248618]
[25]
Nakamura, Y.; Kitagawa, T.; Ihara, H.; Kozaki, S.; Moriyama, M.; Kannan, Y. Potentiation by high potassium of lipopolysaccharide-induced nitric oxide production from cultured astrocytes. Neurochem. Int., 2006, 48(1), 43-49.
[http://dx.doi.org/10.1016/j.neuint.2005.08.002] [PMID: 16188348]
[26]
Nakamura, Y.; Si, Q.S.; Kataoka, K. Lipopolysaccharide-induced microglial activation in culture: temporal profiles of morphological change and release of cytokines and nitric oxide. Neurosci. Res., 1999, 35(2), 95-100.
[http://dx.doi.org/10.1016/S0168-0102(99)00071-1] [PMID: 10616913]
[27]
Kawabe, K.; Takano, K.; Moriyama, M.; Nakamura, Y. Microglia endocytose amyloid b through the binding of transglutaminase 2 and milk fat globule EGF factor 8 protein. Neurochem. Res., 2018, 43(1), 41-49.
[http://dx.doi.org/10.1007/s11064-017-2284-y] [PMID: 28466190]
[28]
Nishimura, Y.; Moriyama, M.; Kawabe, K.; Satoh, H.; Takano, K.; Azuma, Y.T.; Nakamura, Y. Lauric acid alleviates neuroinflammatory responses by activated microglia: Involvement of the GPR40-dependent pathway. Neurochem. Res., 2018, 43(9), 1723-1735.
[http://dx.doi.org/10.1007/s11064-018-2587-7] [PMID: 29947014]
[29]
Pekny, M.; Pekna, M. Reactive gliosis in the pathogenesis of CNS diseases. Biochim. Biophys. Acta, 2016, 1862(3), 483-491.
[http://dx.doi.org/10.1016/j.bbadis.2015.11.014] [PMID: 26655603]
[30]
Walter, L.; Neumann, H. Role of microglia in neuronal degeneration and regeneration. Semin. Immunopathol., 2009, 31(4), 513-525.
[http://dx.doi.org/10.1007/s00281-009-0180-5] [PMID: 19763574]
[31]
Koistinaho, M.; Koistinaho, J. Role of p38 and p44/42 mitogen-activated protein kinases in microglia. Glia, 2002, 40(2), 175-183.
[http://dx.doi.org/10.1002/glia.10151] [PMID: 12379905]
[32]
Pawate, S.; Shen, Q.; Fan, F.; Bhat, N.R. Redox regulation of glial inflammatory response to lipopolysaccharide and interferongamma. J. Neurosci. Res., 2004, 77(4), 540-551.
[http://dx.doi.org/10.1002/jnr.20180] [PMID: 15264224]
[33]
Kim, E.K.; Choi, E.J. Compromised MAPK signaling in human diseases: an update. Arch. Toxicol., 2015, 89(6), 867-882.
[http://dx.doi.org/10.1007/s00204-015-1472-2] [PMID: 25690731]
[34]
Soliman, M.L.; Puig, K.L.; Combs, C.K.; Rosenberger, T.A. Acetate reduces microglia inflammatory signaling in vitro. J. Neurochem., 2012, 123(4), 555-567.
[http://dx.doi.org/10.1111/j.1471-4159.2012.07955.x] [PMID: 22924711]
[35]
Hsieh, H.L.; Yang, C.M. Role of redox signaling in neuroinflammation and neurodegenerative diseases. BioMed Res. Int., 2013, 2013484613
[http://dx.doi.org/10.1155/2013/484613] [PMID: 24455696]
[36]
Mittal, M.; Siddiqui, M.R.; Tran, K.; Reddy, S.P.; Malik, A.B. Reactive oxygen species in inflammation and tissue injury. Antioxid. Redox Signal., 2014, 20(7), 1126-1167.
[http://dx.doi.org/10.1089/ars.2012.5149] [PMID: 23991888]
[37]
Mander, P.; Brown, G.C. Activation of microglial NADPH oxidase is synergistic with glial iNOS expression in inducing neuronal death: a dual-key mechanism of inflammatory neurodegeneration. J. Neuroinflammation, 2005, 2, 20.
[http://dx.doi.org/10.1186/1742-2094-2-20] [PMID: 16156895]
[38]
Qin, L.; Liu, Y.; Wang, T.; Wei, S.J.; Block, M.L.; Wilson, B.; Liu, B.; Hong, J.S. NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J. Biol. Chem., 2004, 279(2), 1415-1421.
[http://dx.doi.org/10.1074/jbc.M307657200] [PMID: 14578353]
[39]
Haslund-Vinding, J.; McBean, G.; Jaquet, V.; Vilhardt, F. NADPH oxidases in oxidant production by microglia: activating receptors, pharmacology and association with disease. Br. J. Pharmacol., 2017, 174(12), 1733-1749.
[http://dx.doi.org/10.1111/bph.13425] [PMID: 26750203]
[40]
Block, M.L. NADPH oxidase as a therapeutic target in Alzheimer’s disease. BMC Neurosci., 2008, 9(Suppl. 2), S8.
[http://dx.doi.org/10.1186/1471-2202-9-S2-S8] [PMID: 19090996]
[41]
Hirrlinger, J.; Gutterer, J.M.; Kussmaul, L.; Hamprecht, B.; Dringen, R. Microglial cells in culture express a prominent glutathione system for the defense against reactive oxygen species. Dev. Neurosci., 2000, 22(5-6), 384-392.
[http://dx.doi.org/10.1159/000017464] [PMID: 11111154]
[42]
Liu, J.; Mori, A. Age-associated changes in superoxide dismutase activity, thiobarbituric acid reactivity and reduced glutathione level in the brain and liver in senescence accelerated mice (SAM): a comparison with ddY mice. Mech. Ageing Dev., 1993, 71(1-2), 23-30.
[http://dx.doi.org/10.1016/0047-6374(93)90032-M] [PMID: 8309281]
[43]
Schulz, J.B.; Lindenau, J.; Seyfried, J.; Dichgans, J. Glutathione, oxidative stress and neurodegeneration. Eur. J. Biochem., 2000, 267(16), 4904-4911.
[http://dx.doi.org/10.1046/j.1432-1327.2000.01595.x] [PMID: 10931172]
[44]
Johnson, W.M.; Wilson-Delfosse, A.L.; Mieyal, J.J. Dysregulation of glutathione homeostasis in neurodegenerative diseases. Nutrients, 2012, 4(10), 1399-1440.
[http://dx.doi.org/10.3390/nu4101399] [PMID: 23201762]
[45]
Zhang, Z.; Guo, Z.; Zhan, Y.; Li, H.; Wu, S. Role of histone acetylation in activation of nuclear factor erythroid 2-related factor 2/heme oxygenase 1 pathway by manganese chloride. Toxicol. Appl. Pharmacol., 2017, 336, 94-100.
[http://dx.doi.org/10.1016/j.taap.2017.10.011] [PMID: 29054681]
[46]
Shih, A.Y.; Johnson, D.A.; Wong, G.; Kraft, A.D.; Jiang, L.; Erb, H.; Johnson, J.A.; Murphy, T.H. Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J. Neurosci., 2003, 23(8), 3394-3406.
[http://dx.doi.org/10.1523/JNEUROSCI.23-08-03394.2003] [PMID: 12716947]
[47]
Baird, L.; Dinkova-Kostova, A.T. The cytoprotective role of the Keap1-Nrf2 pathway. Arch. Toxicol., 2011, 85(4), 241-272.
[http://dx.doi.org/10.1007/s00204-011-0674-5] [PMID: 21365312]
[48]
Stohwasser, R.; Giesebrecht, J.; Kraft, R.; Müller, E.C.; Häusler, K.G.; Kettenmann, H.; Hanisch, U.K.; Kloetzel, P.M. Biochemical analysis of proteasomes from mouse microglia: induction of immunoproteasomes by interferon-gamma and lipopolysaccharide. Glia, 2000, 29(4), 355-365.
[http://dx.doi.org/10.1002/(SICI)1098-1136(20000215)29:4<355::AID-GLIA6>3.0.CO;2-4] [PMID: 10652445]
[49]
Das, A.; Kim, S.H.; Arifuzzaman, S.; Yoon, T.; Chai, J.C.; Lee, Y.S.; Park, K.S.; Jung, K.H.; Chai, Y.G. Transcriptome sequencing reveals that LPS-triggered transcriptional responses in established microglia BV2 cell lines are poorly representative of primary microglia. J. Neuroinflammation, 2016, 13(1), 182.
[http://dx.doi.org/10.1186/s12974-016-0644-1] [PMID: 27400875]
[50]
Cummings, J.H.; Pomare, E.W.; Branch, W.J.; Naylor, C.P.; Macfarlane, G.T. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut, 1987, 28(10), 1221-1227.
[http://dx.doi.org/10.1136/gut.28.10.1221] [PMID: 3678950]
[51]
Bloemen, J.G.; Venema, K.; van de Poll, M.C.; Olde Damink, S.W.; Buurman, W.A.; Dejong, C.H. Short chain fatty acids exchange across the gut and liver in humans measured at surgery. Clin. Nutr., 2009, 28(6), 657-661.
[http://dx.doi.org/10.1016/j.clnu.2009.05.011] [PMID: 19523724]