Depression, one of the most prevalent psychiatric disorders, is characterized by low mood, loss of interest, guilty feelings or low self-esteem, sleep and appetite disorders, anxiety and anhedonia [1, 2], even exposed to increased risk of suicide [3]. Data from the epidemiological investigation have indicated that depression is considered to be the current primary cause of disability worldwide [4]. World Health Organization (WHO) predicts that depression could be the leading cause of the greatest global burden by 2030 [5]. Before 2020, mental disorders have been reported to be the leading causes of the global health-related burden, with depressive and anxiety disorders being leading contributors to this burden. However, the emergence of the coronavirus disease 2019 (COVID-19) pandemic has created an environment where many determinants of poor mental health are exacerbated. It has been reported that throughout 2020, the pandemic led to a 27·6% increase in cases of major depressive disorders and 25·6% increase in cases of anxiety disorders globally [6–8]. Despite these increasing studies and significant economic costs, the pathogenesis and the molecular mechanism underlying depression are still not fully understood [9]. Presently, various different pharmacological approaches have been widely used in the treatment of depression. Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, fluoxetine, or escitalopram, are the clinically first-line antidepressants. However, findings from the clinical investigation have indicated that the response rate (defined as at least a 50% improvement from baseline) to SSRIs is only about 60%, which even is accompanied with confirmed side effects such as nausea, vomiting, or sexual function recession [10–11]. In addition, the experiment observation has reported that fluoxetine treatment could induce anxiogenic-like responses in the animal model of depression [12]. Accordingly, it is sensible to explore effective treatment targets to improve current treatment for depression.
Emerging evidence has reported that the risk for depression is mainly mediated by stressful life events and genetic factors. Stressful life events are considered to be the aggravating triggers of incidence and recurrence of depression [9]. Stress has been considered to be the most prevalently precipitating factors of depression. Stress is a highly personalized phenomenon that varies between people depending on individual genes, development, experience, vulnerability and resilience, and between different types of tasks. Stressors are perceived and processed by the brain which triggers the biological response to stress, and the physiologic responses and behavioral responses are initiated, leading to allostasis and adaptation [13]. Gradually, allostatic load can accumulate, and the overexposure to mediators of neural, endocrine, and immune stress can have adverse effects on various organ systems, which could contribute to depression [14–15]. Previously, emerging evidence has revealed the presence of an intense dialogue between the brain and brain–gut–microbiome axis. The brain–gut–microbiome axis is generally considered to be a bidirectional communication pathway between the gut microbiota and the central nervous system. Data from clinical investigation and experimental study have suggested that the stress-induced activation of neuroinflammation might be involved in the development, maintenance, or exacerbation of depression [16–17].
Accumulating evidence from clinical investigation and experimental study has identified the involvement of the stress-induced activation of inflammation, including neuroinflammation and systemic inflammation in the development and pathogenesis of depression [18–20]. It has been identified that depressive symptoms can be induced in humans with administration of low-dose lipopolysaccharide (LPS), which could activate the innate immune system and trigger the release of inflammatory cytokines [21]. The increased levels of biomarkers of inflammation such as inflammatory cytokines and acute-phase proteins have been found to be reliably elevated in a significant proportion of patients suffered from major depressive disorder (MDD) [22]. The experimental findings have also indicated that the CD-1 mice subjected to the administration of interleukin-1beta (IL-1β) and LPS contributed to depression-like effects in the tail suspension test (TST) and the forced swim test (FST) [23]. A previous studies have also reported that the obviously increased peripheral and central proinflammatory cytokines, including hypothalamus, hippocampus, pituitary and spleen, were induced by exposure to stress in animal model [24], suggesting the specific role of stress-induced inflammatory reaction in the pathogenesis of depression. Our recent studies have also demonstrated that exposure to chronic restraint stress (CRS) triggered the significant activation of microglia and neuroinflammation induced by high mobility group box-1 (HMGB1), and induced depression-like behaviors in rats subjected to CRS [25], which indicated that stress-activated neuroinflammation might be the key pathway linking stress and depression.
Toll-like receptors (TLRs), affiliated to the germline-encoded pattern recognition receptors (PRRs), have been identified to be the important mediators of inflammatory pathways in the pathological process of depression, which plays a major role in the subsequent initiation of immune responses [25–26]. Previously, twelve members of the TLR family have been identified in the mammals [27]. Among the TLR family, toll-like receptor 4 (TLR4) has been demonstrated to be one potential inflammatory regulator which is considered to be associated with MDD [28]. Clinical investigation have shown that increased expression of TLR-4 RNA and protein, as well as NF-κβ are found in newly diagnosed patients with MDD, suggesting the involvement of the stress-induced neuroinflammation mediated by the TLR4 pathway [29–30]. And clinical improvement of depressive symptoms during psychotherapy has been identified to be associated with decreased expression of pro-inflammatory markers mediated by TLR4 [29]. Another clinical study has also reported that TLR mRNA levels were differentially expressed in MDD patient and TLR4 was found to be an independent risk factor associated with the severity of MDD [31]. Findings from the previous studies have reported that the observed abnormalities of proinflammatory cytokines in the brain of suicide victims may be related to an abnormality of TLR4 over-expression [32]. Moreover, results in the animal study has confirmed that LPS from bacterial translocation contributes to the TLR 4 activation in rats subjected to chronic mild stress (CMS), which leads to release of inflammatory mediators offers a potential therapeutic approach for the treatment of depression [33]. Another study has also demonstrated that the inflammatory process driven by TLR4/myeloid differentiation factor88 (MyD88)/ nuclear factor kappa-B (NF-κB) signaling pathway plays a critical role in the chronic unpredictable mild stress (CUMS)-induced depression-like behavior, including the significant decrease in preference for a sucrose solution or in total moving distance [34]. And the antidepressants obviously alleviated CUMS-induced depression-like behavior and exerted considerable neuroprotective effects by regulating the microglial state transition by inhibiting the TLR4/MyD88/NF-κB signaling pathway [34]. Our previous studies about genome-wide transcriptome analysis of hippocampus has also indicated that TLR signaling pathway was involved in the pathogenisis of stress-induced depressive disorder [35].
Currently, data from clinical trials and experimental funding has verified the effectiveness and safety of acupuncture for depression [36–39]. Our preliminary findings have confirmed that acupuncture could regulate the stress-induced activation of neuroinflammation and exert antidepressant effect [25, 40–41], which has also been supported by the data from clinical investigations. However, the mechanism of the antidepressant effect of acupuncture for depression through modulating the stress-induced activation of neuroinflammation mediated by TLR4 signaling pathway has not been fully elucidated. Accordingly, here the rat model in the present study was established by exposure to CRS to simulate depression based on the preliminary research of our team. The expression of the key hippocampal proteins and mRNAs on TLR4 signaling pathway were detected. We aimed to elucidate the mechanisms underlying the antidepressant effect of acupuncture through regulating the upper triggers of the stress-induced activation of neuroinflammation mediated by TLR4 signaling pathway, which might shed new light on conceptual frameworks of prospects for new strategies for depression.