Microglial IL-1β progressively increases with duration of alcohol consumption

  • Bruno Pradier
  • Edda Erxlebe
  • Astrid Markert
  • Ildikó Rácz
Brief Communication
  • 13 Downloads

Abstract

Chronic alcohol abuse leads to severe brain damage. Although the underlying neuropathological processes are largely unknown, recent studies show that chronic alcohol consumption leads to neuroinflammation and may result in neurodegeneration and impaired neuronal connectivity. Long-term alcohol consumption promotes the production of pro-inflammatory cytokines, such as TNF-α and IL-1β, and activates microglia cells in the brain. As it has not yet been investigated to what extent these processes dependent on the duration of alcohol consumption or whether microglia are source of pro-inflammatory cytokines in vivo, this study investigated the expression of the pro-inflammatory cytokine, IL-1β, in microglia at different time points in mice chronically exposed to alcohol. In the present study, we exposed mice to 2, 6, and 12 months of alcohol consumption, and using immunohistochemistry, analyzed the expression of the microglial marker, Iba1, together with the pro-inflammatory cytokine IL-1β in several cortical regions. Moreover, we investigated the effect of pro-inflammatory activation of microglia on neuronal density. We found that alcohol drinking progressively enhanced IL-1β expression in microglia, which was paralleled with an overall increased microglial density after long-term alcohol consumption. However, we did not find changes in the neuronal density or cortical volume after long-term alcohol consumption. These data show that 12 months of alcohol drinking leads to a pro-inflammatory activation of microglia, which may contribute to impaired neuronal connectivity in the cortex. Anti-inflammatory drug treatment during or after chronic alcohol consumption may thus provide a strategy for restoring brain homeostasis.

Keywords

Neuroinflammation Pro-inflammatory cytokine Iba1 Chronic alcohol 

Notes

Acknowledgements

We thank Greta Krusch for helping with the immunostainings and Abigail Polter for the comments on the manuscript.

Author contribution

IR and BP were responsible for the study concept, data analysis, and draft of the manuscript. BP, EE, and AM contributed to the acquisition of animal data.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Alfonso-Loeches S, Pascual-Lucas M, Blanco AM, Sanchez-Vera I, Guerri C (2010) Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. J Neurosci: Off J Soc Neurosci 30(24):8285–8295.  https://doi.org/10.1523/JNEUROSCI.0976-10.2010 CrossRefGoogle Scholar
  2. Alfonso-Loeches S, Pascual M, Guerri C (2013) Gender differences in alcohol-induced neurotoxicity and brain damage. Toxicology 311(1-2):27–34.  https://doi.org/10.1016/j.tox.2013.03.001 CrossRefPubMedGoogle Scholar
  3. Alfonso-Loeches S, Urena-Peralta J, Morillo-Bargues MJ, Gomez-Pinedo U, Guerri C (2016) Ethanol-induced TLR4/NLRP3 neuroinflammatory response in microglial cells promotes leukocyte infiltration across the BBB. Neurochem Res 41(1-2):193–209.  https://doi.org/10.1007/s11064-015-1760-5 CrossRefPubMedGoogle Scholar
  4. Alfonso-Loeches S, Urena-Peralta JR, Morillo-Bargues MJ, Oliver-De La Cruz J, Guerri C (2014) Role of mitochondria ROS generation in ethanol-induced NLRP3 inflammasome activation and cell death in astroglial cells. Front Cell Neurosci 8:216.  https://doi.org/10.3389/fncel.2014.00216 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Chastain LG, Sarkar DK (2014) Role of microglia in regulation of ethanol neurotoxic action. Int Rev Neurobiol 118:81–103.  https://doi.org/10.1016/B978-0-12-801284-0.00004-X CrossRefPubMedGoogle Scholar
  6. Crews FT, Vetreno RP (2016) Mechanisms of neuroimmune gene induction in alcoholism. Psychopharmacology 233(9):1543–1557.  https://doi.org/10.1007/s00213-015-3906-1 CrossRefPubMedGoogle Scholar
  7. Cui C, Noronha A, Warren KR, Koob GF, Sinha R, Thakkar M, Matochik J, Crews FT, Chandler LJ, Pfefferbaum A, Becker HC, Lovinger D, Everitt BJ, Egli M, Mandyam CD, Fein G, Potenza MN, Harris RA, Grant KA, Roberto M, Meyerhoff DJ, Sullivan EV (2015) Brain pathways to recovery from alcohol dependence. Alcohol 49(5):435–452.  https://doi.org/10.1016/j.alcohol.2015.04.006 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Erol A, Karpyak VM (2015) Sex and gender-related differences in alcohol use and its consequences: contemporary knowledge and future research considerations. Drug Alcohol Depend 156:1–13.  https://doi.org/10.1016/j.drugalcdep.2015.08.023 CrossRefPubMedGoogle Scholar
  9. Fernandez-Lizarbe S, Pascual M, Guerri C (2009) Critical role of TLR4 response in the activation of microglia induced by ethanol. J Immunol 183(7):4733–4744.  https://doi.org/10.4049/jimmunol.0803590 CrossRefPubMedGoogle Scholar
  10. Grathwohl SA, Kälin RE, Bolmont T, Prokop S, Winkelmann G, Kaeser SA, Odenthal J, Radde R, Eldh T, Gandy S, Aguzzi A, Staufenbiel M, Mathews PM, Wolburg H, Heppner FL, Jucker M (2009) Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia. Nat Neurosci 12(11):1361–1363.  https://doi.org/10.1038/nn.2432 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Hanisch UK (2013) Proteins in microglial activation—inputs and outputs by subsets. Curr Protein Pept Sci 14(1):3–15.  https://doi.org/10.2174/1389203711314010003 CrossRefPubMedGoogle Scholar
  12. He J, Crews FT (2008) Increased MCP-1 and microglia in various regions of the human alcoholic brain. Exp Neurol 210(2):349–358.  https://doi.org/10.1016/j.expneurol.2007.11.017 CrossRefPubMedGoogle Scholar
  13. Marshall SA, McClain JA, Kelso ML, Hopkins DM, Pauly JR, Nixon K (2013) Microglial activation is not equivalent to neuroinflammation in alcohol-induced neurodegeneration: the importance of microglia phenotype. Neurobiol Dis 54:239–251.  https://doi.org/10.1016/j.nbd.2012.12.016 CrossRefPubMedPubMedCentralGoogle Scholar
  14. McClain JA, Morris SA, Deeny MA, Marshall SA, Hayes DM, Kiser ZM, Nixon K (2011) Adolescent binge alcohol exposure induces long-lasting partial activation of microglia. Brain Behav Immun 25(Suppl 1):S120–S128.  https://doi.org/10.1016/j.bbi.2011.01.006 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Montesinos J, Alfonso-Loeches S, Guerri C (2016) Impact of the innate immune response in the actions of ethanol on the central nervous system. Alcohol Clin Exp Res 40(11):2260–2270.  https://doi.org/10.1111/acer.13208 CrossRefPubMedGoogle Scholar
  16. Morris GP, Clark IA, Zinn R, Vissel B (2013) Microglia: a new frontier for synaptic plasticity, learning and memory, and neurodegenerative disease research. Neurobiol Learn Mem 105:40–53.  https://doi.org/10.1016/j.nlm.2013.07.002 CrossRefPubMedGoogle Scholar
  17. Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates, 4th edn. Academic Press, San DiegoGoogle Scholar
  18. Piccioli P, Rubartelli A (2013) The secretion of IL-1beta and options for release. Semin Immunol 25(6):425–429.  https://doi.org/10.1016/j.smim.2013.10.007 CrossRefPubMedGoogle Scholar
  19. Piyanova A, Albayram O, Rossi CA, Farwanah H, Michel K, Nicotera P, Sandhoff K, Bilkei-Gorzo A (2013) Loss of CB1 receptors leads to decreased cathepsin D levels and accelerated lipofuscin accumulation in the hippocampus. Mech Ageing Dev 134(9):391–399.  https://doi.org/10.1016/j.mad.2013.08.001 CrossRefPubMedGoogle Scholar
  20. Pradier B, Erxlebe E, Markert A, Racz I (2015) Interaction of cannabinoid receptor 2 and social environment modulates chronic alcohol consumption. Behav Brain Res 287:163–171.  https://doi.org/10.1016/j.bbr.2015.03.051 CrossRefPubMedGoogle Scholar
  21. Pradier B, Jeub M, Markert A, Mauer D, Tolksdorf K, van de Putte T, Seuntjens E, Gailus-Durner V, Fuchs H, Hrabě de Angelis M, Huylebroeck D, Beck H, Zimmer A, Rácz I (2014) Smad-interacting protein 1 affects acute and tonic, but not chronic pain. Eur J Pain 18(2):249–257.  https://doi.org/10.1002/j.1532-2149.2013.00366.x CrossRefPubMedGoogle Scholar
  22. Racz I, Markert A, Mauer D, Stoffel-Wagner B, Zimmer A (2013) Long-term ethanol effects on acute stress responses: modulation by dynorphin. Addict Biol 18(4):678–688.  https://doi.org/10.1111/j.1369-1600.2012.00494.x CrossRefPubMedGoogle Scholar
  23. Vetreno RP, Yaxley R, Paniagua B, Crews FT (2016a) Diffusion tensor imaging reveals adolescent binge ethanol-induced brain structural integrity alterations in adult rats that correlate with behavioral dysfunction. Addict Biol 21(4):939–953.  https://doi.org/10.1111/adb.12232 CrossRefPubMedGoogle Scholar
  24. Vetreno RP, Yaxley R, Paniagua B, Johnson GA, Crews FT (2016b) Adult rat cortical thickness changes across age and following adolescent intermittent ethanol treatment. Addict Biol 22(3):712–723.  https://doi.org/10.1111/adb.12364 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Zahr NM, Pfefferbaum A, Sullivan EV (2017) Perspectives on fronto-fugal circuitry from human imaging of alcohol use disorders. Neuropharmacology 122:189–200.  https://doi.org/10.1016/j.neuropharm.2017.01.018 CrossRefPubMedGoogle Scholar
  26. Zou J, Crews FT (2012) Inflammasome-IL-1beta signaling mediates ethanol inhibition of hippocampal neurogenesis. Front Neurosci 6:77.  https://doi.org/10.3389/fnins.2012.00077 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of Molecular PsychiatryUniversity of Bonn Medical CenterBonnGermany
  2. 2.Department of Molecular Pharmacology, Physiology and BiotechnologyBrown UniversityProvidenceUSA
  3. 3.Clinic for Neurodegenerative Diseases and GerontopsychiatryUniversity of Bonn Medical CenterBonnGermany

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