Pascual María, Baliño Pablo, Aragón Carlos M G, Guerri Consuelo
Department of Molecular and Cellular Pathology of Alcohol, Príncipe Felipe Research Center, C/ Eduardo Primo Yúfera, 3, 46012 Valencia, Spain.
Neuropharmacology. 2015 Feb;89:352-9. doi: 10.1016/j.neuropharm.2014.10.014.
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.
近期证据支持神经免疫系统激活对行为的影响。我们已经证明，乙醇通过刺激神经胶质细胞中的Toll样受体4（TLR4）信号通路激活先天免疫系统，这会触发炎症介质的释放并导致神经炎症。本研究旨在评估乙醇诱导的细胞因子和趋化因子上调是否与乙醇清除24小时后的焦虑相关行为有关，以及TLR4或TLR2是否参与这些效应。我们使用用酒精处理5个月的野生型（WT）、TLR4基因敲除（KO）和TLR2基因敲除小鼠，以表明长期摄入乙醇会增加野生型小鼠纹状体和血清（MCP-1、MIP-1α、CX3CL1）中细胞因子（IL-1β、IL-17、TNF-α）和趋化因子（MCP-1、MIP-1α、CX3CL1）的水平。剥夺乙醇24小时会诱导纹状体中的IFN-γ水平，并使该脑区中的一些细胞因子（IL-1β、IL-17）和趋化因子（MIP-1α、CX3CL1）维持在高水平。通过暗箱和明箱试验以及高架十字迷宫试验评估，后述这些事件与焦虑相关行为的增加有关。值得注意的是，缺乏TLR4或TLR2受体的小鼠在很大程度上可免受乙醇诱导的细胞因子和趋化因子释放以及戒酒期间行为相关效应的影响。这些数据支持TLR4和TLR2反应在神经炎症以及乙醇剥夺期间焦虑相关行为效应中的作用，并且还提供了证据表明趋化因子和细胞因子可以作为乙醇诱导的神经免疫反应的生物标志物。
