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

Published: 01-07-2018| Version 1 | DOI: 10.17632/2tyyncv6rm.1
Xiang 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


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.