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

Abstract

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