Abstract
IntroductionA growing body of evidence suggests that stress is an important factor in depression, and pro‐inflammatory cytokines contribute to the occurrence and development of depression in both animal models and human patients. Toll‐like receptor 4 (TLR4) has been shown to be a key innate immune pattern recognition receptor involved in the regulation of stress responses and inflammation. However, the exact effects of TLR4 on depressive‐like behaviors induced by chronic social defeat stress (CSDS) are not known.MethodsIn this study, the effects of TLR4 on depressive‐like behaviors were investigated in an animal model of depression induced by CSDS. The depressive‐like behaviors were assessed by forced swimming test (FST), social interaction test (SIT), and light–dark box test (LDT). The protein expressions of TLR4 and tumor necrosis factor‐α (TNF‐α) in the hippocampus were measured using Western blotting.ResultsWe found that CSDS increased TLR4 protein levels in the hippocampus and induced behavioral despair in FST, social avoidance in SIT, and anxiety‐like behavior in LDT. Fluoxetine normalized the increased expression of TLR4 and reversed behavioral despair, social avoidance, as well as anxiety‐like behavior induced by CSDS. However, directly blocking TLR4, by using either TLR4 inhibitor TAK‐242 or knockout of TLR4, only inhibited behavioral despair, but not social avoidance or anxiety‐like behavior induced by CSDS.ConclusionsThese results demonstrate a specific modulating role of TLR4 in behavioral despair induced by CSDS and suggest that TAK‐242 may be a beneficial treatment for patients with behavioral despair.
Highlights
A growing body of evidence suggests that stress is an important factor in depression, and pro-inflammatory cytokines contribute to the occurrence and development of depression in both animal models and human patients
We found that chronic social defeat stress (CSDS) resulted in depressivelike behaviors including increased immobility duration in forced swimming test (FST), decreased social interaction ratio in social interaction test (SIT), and decreased time spent in the light area in light–dark box test (LDT), accompanied by increased Toll-like receptor 4 (TLR4) protein level in hippocampus
Our findings showed that fluoxetine reversed behavioral despair, social avoidance, and anxiety-like behavior, and normalized increased expression of hippocampal TLR4 induced by CSDS
Summary
Depression is a severe and chronic mental illness. It is characterized by sadness, anhedonia, low self-esteem, fatigue, disturbed sleep or appetite, and poor concentration. By recognizing exogenous pathogen-associated molecular patterns (PAMPs) such as LPS, TLR4 triggers production of pro-inflammatory cytokines, including TNF-α, which are downstream signaling molecules of TLR4 (Liu et al, 2014). TLR4-specific inhibitor reversed anhedonia induced by chronic unpredictable mild stress (Wang, Xu, Liu, Li, & Li, 2018). These studies imply potential roles of TLR4 in depression induced by stress. Since hippocampus is considered to be one of the most important areas involved in stress and depression, and our previous study has demonstrated that TNF-α is a common risk factor in depressive disorders induced by both stress and inflammation (Guan, Lin, & Tang, 2015), expression of hippocampal TLR4 as well as TNF-α was examined in the current study
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