The Innate Immune Receptors TLR2/4 Mediate Repeated Social Defeat Stress-Induced Social Avoidance through Prefrontal Microglial Activation

• Published in: Neuron (Cambridge, Mass.) Mass.), 2018-08, Vol.99 (3), p.464-479.e7
• Main Authors: Nie, Xiang, Kitaoka, Shiho, Tanaka, Kohei, Segi-Nishida, Eri, Imoto, Yuki, Ogawa, Atsubumi, Nakano, Fumitake, Tomohiro, Ayaka, Nakayama, Kazuki, Taniguchi, Masayuki, Mimori-Kiyosue, Yuko, Kakizuka, Akira, Narumiya, Shuh, Furuyashiki, Tomoyuki
• Format: Article
• Language: English
• Subjects: Anxiety; Atrophy; Brain research; depression; Environmental stress; Gene expression; Genetic engineering; Inflammation; innate immune receptor; Innate immunity; Ligands; medial prefrontal cortex; Mental depression; Metabolism; Microglia; MicroRNAs; Neurons; Prefrontal cortex; Rodents; Social interaction; Social interactions; Software; Statistical analysis; stress; TLR2 protein; TLR4 protein; Toll-like receptor; Toll-like receptors; Tumor necrosis factor-α
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2018.06.035

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. [Display omitted] •Repeated stress activates mPFC microglia through innate immune receptors TLR2/4•Activated microglia induce response attenuation and atrophy of mPFC neurons•Activated microglia underlie repeated stress-induced social avoidance•TLR2/4 induce IL-1α and TNF-α in mPFC microglia, leading to social avoidance 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.