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: Nie et al. identify TLR2/4 as crucial mediators of repeated stress-induced microglial activation in the mPFC, which leads to neuronal and behavioral changes through inflammation-related cytokines. These results highlight pivotal roles of innate immunity in the mPFC in repeated stress.
CITATION STYLE
Nie, X., Kitaoka, S., Tanaka, K., Segi-Nishida, E., Imoto, Y., Ogawa, A., … Furuyashiki, T. (2018). The Innate Immune Receptors TLR2/4 Mediate Repeated Social Defeat Stress-Induced Social Avoidance through Prefrontal Microglial Activation. Neuron, 99(3), 464-479.e7. https://doi.org/10.1016/j.neuron.2018.06.035
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