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

Authors:
Shiho Kitaoka
Shiho Kitaoka
Kyoto University Graduate School of Medicine
Japan
Kohei Tanaka
Kohei Tanaka
Tottori University Graduate School of Medical Science
Japan
Eri Segi-Nishida
Eri Segi-Nishida
Kyoto University
Japan
Yuki Imoto
Yuki Imoto
Kyoto University Graduate School of Medicine
Japan

Neuron 2018 Aug 19;99(3):464-479.e7. Epub 2018 Jul 19.

Division of Pharmacology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan; AMED-CREST, Chiyoda-ku, Tokyo 100-0004, Japan. Electronic address:

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.

Abstract Video

Roles of TLR2/4 in Prefrontal Microglia for Repeated Stress


Source: Cell Press

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http://dx.doi.org/10.1016/j.neuron.2018.06.035DOI Listing

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August 2018
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