Division of Pharmacology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan; CREST Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Kyoto 606-8509, Japan; Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies, Kyoto, Kyoto 606-8501, Japan; AMED-CREST, Chiyoda-ku, Tokyo 100-0004, Japan.
Division of Pharmacology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan; AMED-CREST, Chiyoda-ku, Tokyo 100-0004, Japan.
Neuron. 2018 Aug 8;99(3):464-479.e7. doi: 10.1016/j.neuron.2018.06.035. Epub 2018 Jul 19.
Repeated environmental stress has been proposed to induce neural inflammation together with depression and anxiety. Innate immune receptors, such as Toll-like receptors (TLRs), are activated by exogenous or endogenous ligands to evoke inflammation. Here we show that the loss of TLR2 and TLR4 (TLR2/4) abolished repeated social defeat stress (R-SDS)-induced social avoidance and anxiety in mice. TLR2/4 deficiency mitigated R-SDS-induced neuronal response attenuation, dendritic atrophy, and microglial activation in the medial prefrontal cortex (mPFC). Furthermore, mPFC microglia-specific TLR2/4 knockdown blocked social avoidance. Transcriptome analyses revealed that R-SDS induced IL-1α and TNF-α in mPFC microglia in a TLR2/4-dependent manner, and antibody blockade of these cytokines in the mPFC suppressed R-SDS-induced social avoidance. These results identify TLR2/4 as crucial mediators of R-SDS-induced microglial activation in the mPFC, which leads to neuronal and behavioral changes through inflammation-related cytokines, highlighting unexpected pivotal roles of innate immunity in the mPFC in repeated environmental stress-induced behavioral changes. VIDEO ABSTRACT.
反复的环境应激被认为会引起神经炎症，同时伴随着抑郁和焦虑。先天免疫受体，如 Toll 样受体 (TLRs)，被外源性或内源性配体激活，引发炎症。在这里，我们发现 TLR2 和 TLR4（TLR2/4）的缺失消除了重复社交挫败应激（R-SDS）诱导的小鼠社交回避和焦虑。TLR2/4 缺失减轻了 R-SDS 诱导的内侧前额叶皮质（mPFC）神经元反应减弱、树突萎缩和小胶质细胞激活。此外，mPFC 小胶质细胞特异性 TLR2/4 敲低阻断了社交回避。转录组分析显示，R-SDS 以 TLR2/4 依赖的方式诱导 mPFC 小胶质细胞中的 IL-1α 和 TNF-α，并且 mPFC 中这些细胞因子的抗体阻断抑制了 R-SDS 诱导的社交回避。这些结果表明 TLR2/4 是 R-SDS 诱导的 mPFC 中小胶质细胞激活的关键介质，通过炎症相关细胞因子导致神经元和行为变化，突出了先天免疫在重复环境应激诱导的行为变化中在 mPFC 中的意外关键作用。
