A study of TLR2/4 in repeated social defeat stress. Nie, Kitaoka, Tanaka et al.

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 medial prefrontal cortex (mPFC). Furthermore, mPFC microglia-specific TLR2/4 knockdown blocked the social avoidance. Transcriptome analyses revealed that R-SDS induced IL-1α and TNFα in mPFC microglia in a TLR2/4-dependent manner, and antibody blockade of these cytokines in mPFC suppressed R-SDS-induced social avoidance. These results identify TLR2/4 as crucial mediators of R-SDS-induced microglial activation in mPFC, which leads to neuronal and behavioral changes through inflammation-related cytokines, thus highlighting unexpected pivotal roles of innate immunity in mPFC in repeated environmental stress-induced behavioral changes.

反复的环境应激被提出可诱导神经炎症，并伴随抑郁与焦虑症状。先天免疫受体，如 Toll 样受体（TLRs），在病原体相关分子模式（PAMPs）或损伤相关分子模式（DAMPs）的激活下引发炎症反应。本研究揭示，TLR2 和 TLR4（TLR2/4）的缺失消除了重复社会挫败应激（R-SDS）诱导的小鼠社会回避和焦虑。TLR2/4 缺陷减轻了 R-SDS 诱导的内侧前额叶皮层（mPFC）神经元反应减弱、树突萎缩和胶质细胞激活。此外，mPFC 胶质细胞特异性 TLR2/4 敲低阻断了社会回避行为。转录组分析显示，R-SDS 通过 TLR2/4 依赖性机制诱导 mPFC 胶质细胞中 IL-1α 和 TNFα 的表达，且在 mPFC 中对这些细胞因子进行抗体阻断可抑制 R-SDS 诱导的社会回避。这些结果将 TLR2/4 确认为 R-SDS 诱导 mPFC 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，从而突显了先天免疫在内侧前额叶皮层中在反复环境应激诱导的行为改变中意想不到的关键作用。