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.