Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior.
Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior.
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DOI：
10.1016/j.bbi.2015.12.012
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Beurel E
中科院分区：
文献类型：
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作者：
Cheng Y;Pardo M;Armini RS;Martinez A;Mouhsine H;Zagury JF;Jope RS;Beurel E
大多数精神和神经疾病都因压力而恶化。因为这可能部分是由于应激诱导的炎症，我们研究了参与这种应激反应的因素。在一个范例的不可避免的脚休克压力，导致习得性无助抑郁样行为，18个细胞因子和趋化因子增加小鼠海马，峰值6至12小时后的压力。24小时前预处理应力加速应激诱导的海马细胞因子和趋化因子增加的速率，其中大多数在1至3小时后达到峰值水平，通常不改变最大水平。Toll样受体4（TLR 4）参与了这种反应，因为大多数应激诱导的海马细胞因子和趋化因子在TLR 4敲除小鼠中减弱。应激激活野生型小鼠海马中的糖原合成酶激酶-3（GSK 3），但在TLR 4敲除小鼠中没有。抗抑郁药氟西汀或GSK 3抑制剂TDZD-8的管理减少了大多数海马细胞因子和趋化因子的应激诱导的增加。应激增加了海马组织中高迁移率族蛋白1（HMGB 1）的水平，激活了炎症转录因子NF-κB和NLRP 3炎性体。HMGB 1的敲低阻断了由两次连续应激引起的海马中细胞因子和趋化因子增加的加速。氟西汀治疗阻断了应激诱导的HMGB 1上调和随后的NF-κB活化，而TDZD-8给药减弱了HMGB 1下游的NF-κB活化。为了测试压力诱导的细胞因子和趋化因子是否有助于抑郁样行为，评估了习得性无助模型。TNFα的拮抗作用适度降低了对习得性无助诱导的易感性，而TLR 4敲除小鼠对习得性无助具有抗性。因此，应激诱导小鼠海马中广泛的炎症反应，涉及TLR 4，GSK 3和下游炎症信号传导，这些应激反应有助于小鼠对抑郁样行为的易感性。
Most psychiatric and neurological diseases are exacerbated by stress. Because this may partially result from stress-induced inflammation, we examined factors involved in this stress response. After a paradigm of inescapable foot shock stress that causes learned helplessness depression-like behavior, eighteen cytokines and chemokines increased in mouse hippocampus, peaking 6 to 12 hr after stress. A 24 hr prior pre-conditioning stress accelerated the rate of stress-induced hippocampal cytokine and chemokine increases, with most reaching peak levels after 1 to 3 hr, often without altering the maximal levels. Toll-like receptor 4 (TLR4) was involved in this response because most stress-induced hippocampal cytokines and chemokines were attenuated in TLR4 knockout mice. Stress activated glycogen synthase kinase-3 (GSK3) in wild-type mouse hippocampus, but not in TLR4 knockout mice. Administration of the antidepressant fluoxetine or the GSK3 inhibitor TDZD-8 reduced the stress-induced increases of most hippocampal cytokines and chemokines. Stress increased hippocampal levels of the danger-associated molecular pattern (DAMP) protein high mobility group box 1 (HMGB1), activated the inflammatory transcription factor NF-κB, and the NLRP3 inflammasome. Knockdown of HMGB1 blocked the acceleration of cytokine and chemokine increases in the hippocampus caused by two successive stresses. Fluoxetine treatment blocked stress-induced up-regulation of HMGB1 and subsequent NF-κB activation, whereas TDZD-8 administration attenuated NF-κB activation downstream of HMGB1. To test if stress-induced cytokines and chemokines contribute to depression-like behavior, the learned helplessness model was assessed. Antagonism of TNFα modestly reduced susceptibility to learned helplessness induction, whereas TLR4 knockout mice were resistant to learned helplessness. Thus, stress-induces a broad inflammatory response in mouse hippocampus that involves TLR4, GSK3, and downstream inflammatory signaling, and these stress responses contribute to susceptibility to depression-like behavior in mice.