Elsevier

Journal of Affective Disorders

Volume 271, 15 June 2020, Pages 262-271
Journal of Affective Disorders

Research paper
Major depression accompanied with inflammation and multiple cytokines alterations: Evidences from clinical patients to macaca fascicularis and LPS-induced depressive mice model

https://doi.org/10.1016/j.jad.2020.03.131Get rights and content

Highlights

  • The levels of IL-6, IL-8, MCP-1 and VEGF were elevated in the serum of MDD patients and NOD macaca fascicularis.

  • The aLPS and cLPS depressed mice displayed higher serum concentrations of IL-6 and VEGF than these in control mice.

  • The prefrontal cortex of the LPS-treated mice showed increased expressions of IL-6 and VEGF.

  • The IL-6 and VEGF may as predictive biomarkers for novel diagnostic as well as therapeutic of depression.

  • The hypothalamus may as a key brain region involve in the inflammation related depressive-like behaviors.

Abstract

Background

Inflammation progress has been consistently implicated in the pathophysiology of major depressive disorder (MDD). However, the underlying mechanism of inflammation and depressive symptoms still far from being fully elucidated. In addition, studies on emotional disorders could also benefit from model of the non-human primates. To explore the difference of serum multi-cytokines levels among the MDD patients and depressed macaca fascicularis as well as LPS-treated mice, thus may find the reliable potential biomarkers for MDD.

Methods

Serum multi-cytokines levels among MDD patients (n = 44) and depressed macaca fascicularis (n = 6) together with controls (n = 22 for human, n = 6 for macaques) were detected by the Bio-Plex cytokines panel. Then five of these serum cytokines in LPS-treated mice were measured via ELISA. Furthermore, these cytokines protein expressions were validated by western blotting in three depression-related regions of LPS-treated mice.

Results

Here, we found that MDD patients displayed increased concentration of 13 proinflammatory and anti-inflammatory cytokines accompanied with one decreased cytokine in peripheral serum. Meanwhile, the naturally occurring depression (NOD) macaca fascicularis merely exhibited elevated concentration of 4 peripheral cytokines (IL-6, IL-8, MCP-1, VEGF), which were in accordance with the outcomes of MDD patients. Importantly, the serum and brain tissues of LPS-treated mice also emerged similar cytokines alterations.

Conclusion

In summary, our findings strengthen the evidence that cytokines were associated with the depression, and the IL-6 and VEGF may as predictive biomarkers for novel diagnostic as well as therapeutic of depression. The hypothalamus may as a key brain region involve in the inflammatory related depressive-like behaviors.

Introduction

Major depressive disorder (MDD) is a prevalent psychiatric disease, which affects 16% of the world population (consortium, 2015). MDD is characterized by profound disturbances in mood and accompanied with other symptoms such as anhedonia, feeling of hopelessness and disrupted sleeping. Despite there are numerous evidences indicate that MDD status exhibits multiple cellular and molecular changes, the underlying pathogenic mechanism still remains elusive (Kalueff et al., 2006; Sahay and Hen, 2007; Seo et al., 2017). The clinical and preclinical studies suggest that the immune activation and inflammation are closely associated with the development of depression (Leng et al., 2018; Beurel et al., 2013; Beydoun et al., 2019; Syed et al., 2018). However, the translational validation of inflammatory markers in humans and different animal models of depressive-like behaviors is still poorly known.

It is well known that proinflammatory cytokines could directly contribute to the pathophysiology of MDD, such as IL-1β, IL-6, IL-17A, TNF-α and so on (Syed et al., 2018; Dowlati et al., 2010; Maes et al., 1997; Pan et al., 2014). In particular, numerous studies have illustrated that peripheral inflammation emergence along with proinflammatory cytokines elevated were frequently associated with MDD patients (Dowlati et al., 2010; Maes et al., 1997; Young et al., 2014). In addition, many other anti-inflammatory cytokines, chemokines, growth factors and other cytokines were also associated with the development of depressive symptoms (Syed et al., 2018; Kohler et al., 2017; Xie et al., 2017; Leighton et al., 2018). With this mind on, we primarily detected these serum multi-cytokines levels among MDD patients and healthy controls (HC). Nevertheless, current studies are short of data on the non-human primates (Felger et al., 2007). Herein, we simultaneously explored the alterations of serum multi-cytokines in naturally occurring depression (NOD) macaca fascicularis.

Recently, human-based studies have demonstrated that depression is highly prevalent in patients suffering from inflammatory diseases. To mimic depressive-like behaviors were modulated by inflammation, we conducted the acute and chronic lipopolysaccharide (aLPS and cLPS) depression mice models. Herein, to explore the cytokines alterations of serum in aLPS and cLPS mice, we employed 1-day LPS and 7-day LPS mice depression models at the same time.

MDD is a psychiatric disorder and typical heterogeneity disease, and its pathophysiology involves in many brain regions. In addition, inflammatory cytokines may alter in both peripheral serum and brain tissues. Evidences from current studies indicated that there was an intimate association among the hippocampus, prefrontal cortex, hypothalamus and the LPS-induce depressive behaviors (Li et al., 2017; Zhang et al., 2014; He et al., 2019). Particularly, the synthesis and release of cytokines or chemokines are highly correlated with the hyperactivity of hypothalamus. Based on the outcomes of peripheral serum, we mainly focused on the aberrant cytokines in these three depression-related target brain regions. Taken together, from human to non-human and mice, from the peripheral serum to brain tissues, we further determined which cytokines may as biomarkers of MDD.

Section snippets

Participants

All the male and female participants were recruited from the First Affiliated Hospital of Chongqing Medical University. The qualified patients enrolled in this study were adult outpatients 22–31 years of age who met the DSM-IV criteria. The single depressed episode and the severity of MDD were assessed by Hamilton depression Rating scale (HDRS). Depressed patients gaining total scores ≥16 were eventually enrolled in this research. MDD patients with other complicated situations such as history

Depressive-like behaviors were successfully induced by cLPS and aLPS

As illustrated in the experimental timelines (Fig. 1), we primarily established cLPS and aLPS models to induce depressive-like behaviors in mice. Compared to control mice, LPS administration resulted in significantly decreased in body weight of cLPS and aLPS mice (Fig. 2A and 2D). The LPS injection also elicited anhedonia of mice, showing as significantly decreased sucrose preference when compared to control mice (Fig. 2B and 2E). Furthermore, LPS-treated mice displayed longer immobile time

Discussion

Numerous studies have already suggested that MDD was commonly accompanied with immune dysregulation and elevation of inflammatory cytokines (Young et al., 2014; Miller and Raison, 2016; Dantzer et al., 2008). In this study, we mainly adopted profiling the multiplex cytokines panel to measure serum cytokines levels of MDD patients and depressed macaca fascicularis. Based on the positive outcomes of human and macaques, we further validated the peripheral serum cytokines concentration of cLPS and

Limitations

There are still some inevitable limitations for the conclusion. Firstly, the BMI of participants with MDD may be as a potential source of heterogeneity. Secondly, the NOD depressed monkeys model just enrolled in the female macaca fascicularis, our results lacking of the male NOD related data. Furthermore, the sample size of macaca fascicularis was also limited, which just met the basic criterion and reflected the content of our research to some degree. In further research, we plan to enlarge

Conclusion

In conclusion, our study mainly found that the IL-6, IL-8, MCP-1 and VEGF were significantly increased in the serum of MDD patients and NOD monkeys. Meanwhile, the serum levels of IL-6 and VEGF were remarkably elevated in cLPS and aLPS mice. Interestingly, the hypothalamic multi-cytokines expression emerged significantly increased levels. Taken together, our findings revealed that the IL-6 and VEGF may be regarded as reliable biomarkers of depression. The hypothalamus also may play a key role

Funding

This work was supported by the National Key Research and Development Program of China (2017YFA0505700) as well as the National Key Program International Cooperation Project (No. 81,820,108,015).

CRediT authorship contribution statement

Yong He: Writing - original draft. Wei Li: Methodology. Yue Wang: Methodology. Yu Tian: Methodology. Xi Chen: Methodology. Zhonghao Wu: Validation. Tianlan Lan: Investigation. Yan Li: Investigation. Mengge Bai: Conceptualization, Methodology. Jie Liu: Methodology. Ke Cheng: Conceptualization. Peng Xie: Funding acquisition.

Declaration of Competing Interest

All authors have declared no conflicts of interest.

Acknowledgments

This work was supported by the National Key Research and Development Program of China (2017YFA0505700) as well as the National Key Program International Cooperation Project (No. 81,820,108,015).

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