Cytokines and chemokines as biomarkers of ethanol-induced neuroinflammation and anxiety-related behavior: Role of TLR4 and TLR2

Recent evidence supports the influence of neuroimmune system activation on behavior. We have demonstrated that ethanol activates the innate immune system by stimulating toll-like receptor 4 (TLR4) signaling in glial cells, which triggers the release of inflammatory mediators and causes neuroinflamma...

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Veröffentlicht in:Neuropharmacology 2015-02, Vol.89, p.352-359
Hauptverfasser: Pascual, María, Baliño, Pablo, Aragón, Carlos M.G., Guerri, Consuelo
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Baliño, Pablo
Aragón, Carlos M.G.
Guerri, Consuelo
description Recent evidence supports the influence of neuroimmune system activation on behavior. We have demonstrated that ethanol activates the innate immune system by stimulating toll-like receptor 4 (TLR4) signaling in glial cells, which triggers the release of inflammatory mediators and causes neuroinflammation. The present study aimed to evaluate whether the ethanol-induced up-regulation of cytokines and chemokines is associated with anxiety-related behavior, 24 h after ethanol removal, and if TLR4 or TLR2 is involved in these effects. We used WT, TLR4-KO and TLR2-KO mice treated with alcohol for 5 months to show that chronic ethanol consumption increases the levels of cytokines (IL-1β, IL-17, TNF-α) and chemokines (MCP-1, MIP-1α, CX3CL1) in the striatum and serum (MCP-1, MIP-1α, CX3CL1) of WT mice. Alcohol deprivation for 24 h induces IFN-γ levels in the striatum and maintains high levels of some cytokines (IL-1β, IL-17) and chemokines (MIP-1α, CX3CL1) in this brain region. The latter events were associated with an increase in anxiogenic-related behavior, as evaluated by the dark and light box and the elevated plus maze tests. Notably, mice lacking TLR4 or TLR2 receptors are largely protected against ethanol-induced cytokine and chemokine release, and behavioral associated effects during alcohol abstinence. These data support the role of TLR4 and TLR2 responses in neuroinflammation and in anxiogenic-related behavior effects during ethanol deprivation, and also provide evidence that chemokines and cytokines can be biomarkers of ethanol-induced neuroimmune response. •Ethanol treatment increases cytokine and chemokine levels in brain and serum.•Ethanol-deprivation changes brain cytokine levels and induces anxiety behavior.•The results highlight the role of neuroimmune/TLRs activation in cytokine production and anxiogenic-like effects in withdrawal.
doi_str_mv 10.1016/j.neuropharm.2014.10.014
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We have demonstrated that ethanol activates the innate immune system by stimulating toll-like receptor 4 (TLR4) signaling in glial cells, which triggers the release of inflammatory mediators and causes neuroinflammation. The present study aimed to evaluate whether the ethanol-induced up-regulation of cytokines and chemokines is associated with anxiety-related behavior, 24 h after ethanol removal, and if TLR4 or TLR2 is involved in these effects. We used WT, TLR4-KO and TLR2-KO mice treated with alcohol for 5 months to show that chronic ethanol consumption increases the levels of cytokines (IL-1β, IL-17, TNF-α) and chemokines (MCP-1, MIP-1α, CX3CL1) in the striatum and serum (MCP-1, MIP-1α, CX3CL1) of WT mice. Alcohol deprivation for 24 h induces IFN-γ levels in the striatum and maintains high levels of some cytokines (IL-1β, IL-17) and chemokines (MIP-1α, CX3CL1) in this brain region. The latter events were associated with an increase in anxiogenic-related behavior, as evaluated by the dark and light box and the elevated plus maze tests. Notably, mice lacking TLR4 or TLR2 receptors are largely protected against ethanol-induced cytokine and chemokine release, and behavioral associated effects during alcohol abstinence. These data support the role of TLR4 and TLR2 responses in neuroinflammation and in anxiogenic-related behavior effects during ethanol deprivation, and also provide evidence that chemokines and cytokines can be biomarkers of ethanol-induced neuroimmune response. •Ethanol treatment increases cytokine and chemokine levels in brain and serum.•Ethanol-deprivation changes brain cytokine levels and induces anxiety behavior.•The results highlight the role of neuroimmune/TLRs activation in cytokine production and anxiogenic-like effects in withdrawal.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>25446779</pmid><doi>10.1016/j.neuropharm.2014.10.014</doi><tpages>8</tpages></addata></record>
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subjects Adaptation, Ocular - drug effects
Adaptation, Ocular - genetics
Animals
Anxiety
Anxiety - chemically induced
Anxiety - metabolism
Biomarkers - metabolism
Central Nervous System Depressants - adverse effects
Cytokines
Cytokines - metabolism
Disease Models, Animal
Encephalitis - chemically induced
Encephalitis - metabolism
Ethanol
Ethanol - adverse effects
Gene Expression Regulation - drug effects
Gene Expression Regulation - genetics
Male
Maze Learning - drug effects
Mice, Inbred C57BL
Mice, Knockout
Neuroinflammation
TLR4
Toll-Like Receptor 2 - genetics
Toll-Like Receptor 2 - metabolism
Toll-Like Receptor 4 - genetics
Toll-Like Receptor 4 - metabolism
Withdrawal
title Cytokines and chemokines as biomarkers of ethanol-induced neuroinflammation and anxiety-related behavior: Role of TLR4 and TLR2
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