The Innate Immune Receptors TLR2/4 Mediate Repeated Social Defeat Stress-Induced Social Avoidance through Prefrontal Microglial Activation
2018; Cell Press; Volume: 99; Issue: 3 Linguagem: Inglês
10.1016/j.neuron.2018.06.035
ISSN1097-4199
AutoresXiang Nie, Shiho Kitaoka, Kohei Tanaka, Eri Segi‐Nishida, Yuki Imoto, Atsubumi Ogawa, Fumitake Nakano, Ayaka Tomohiro, Kazuki Nakayama, Masayuki Taniguchi, Yuko Mimori‐Kiyosue, Akira Kakizuka, Shuh Narumiya, Tomoyuki Furuyashiki,
Tópico(s)Stress Responses and Cortisol
ResumoSummary 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
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