title: Cytokines and chemokines as biomarkers of ethanol-induced neuroinflammation and anxiety-related behavior: role of TLR4 and TLR2.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Pathology of Alcohol, Príncipe Felipe Research Center, C/ Eduardo Primo Yúfera, 3, 46012 Valencia, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Pascual
authors.forename: Pablo
authors.initials: P
authors.lastname: Baliño
authors.forename: Carlos M G
authors.initials: CM
authors.lastname: Aragón
authors.forename: Consuelo
authors.initials: C
authors.lastname: Guerri
mesh_terms: D000221:Adaptation, Ocular / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000009:adverse effects; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism*; D000431:Ethanol / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D002492:Central Nervous System Depressants; D016207:Cytokines; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000431:Ethanol