Assessing the causal relationship between immune cell traits and depression by Mendelian randomization analysis.

BACKGROUND: Observational studies suggested that immune system disorder is associated with depression. However, the causal association has not been fully elucidated. Thus, we aim to assess the causality of the associations of immune cell profiles with risk of depression through Mendelian randomization analysis. METHODS: We extracted genetic variances of immune cell traits from a large publicly available genome-wide association study (GWAS) involving 3757 participants and depression from a GWAS containing 246,363 cases and 561,190 controls of European ancestry. Inverse variance weighting (IVW) was performed as the MR primary analysis. Simultaneously apply MR-Egger and weighted median as supplementary enhancements to the final result. We further performed heterogeneity and horizontal pleiotropy test to validate the main MR results. RESULTS: Five immunophenotypes were identified to be significantly associated with depression risk: CD27 on IgD-CD38dimB cell (OR = 1.019, 95 % CI = 1.010-1.028, P = 1.24 × 10-5), CD45RA-CD4+T cell Absolute Count (OR = 0.974, 95 % CI = 0.962-0.986, P = 3.88 × 10-5), CD40 on CD14-CD16+monocyte (OR = 0.987, 95 % CI = 0.981-0.993, P = 2.1 × 10-4), CD27 on switched memory B cell (OR = 1.015, 95 % CI = 1.006-1.023, P = 2.6 × 10-4), CD27 on IgD-CD38-B cell (OR = 1.017, 95 % CI = 1.008-1.027, P = 3.1 × 10-4). CONCLUSION: Our findings shed light on the intricate interaction pattern between the immune system and depression, offering a novel direction for researchers to investigate the underlying biological mechanisms of depression.

NMDAR (2C) deletion in astrocytes relieved LPS-induced neuroinflammation and depression.

The link between neuroinflammation and depression is a subject of growing interest in neuroscience and psychiatry; meanwhile, the precise mechanisms are still being unrevealed. However, glial cell activation, together with cytokine level elevation, suggests a connection between neuroinflammation and the development or exacerbation of depression. Glial cells (astrocytes) communicate with neurons via their extracellular neurotransmitter receptors, including glutamate receptors NMDARs. However, these receptor roles are controversial and enigmatic in neurological disorders, including depression. Therefore, we hypothesized whether NMDAR subnit NR2C deletion in the astrocytes exhibited anti-depressive effects concurrent with neuroinflammation prevention. To assess, we prepared astrocytic-NR2C knockout mice (G-2C: GFAPCre+Grin2Cflox/flox), followed by LPS administration, behavior tests, and biochemical analysis. Stimulatingly, astrocytic-NR2C knockout mice (G-2C) did not display depressive-like behaviors, neuroinflammation, and synaptic deficits upon LPS treatment. PI3K was impaired upon LPS administration in control mice (Grin2Cflox/flox); however, they were intact in the hippocampus of LPS-treated G-2C mice. Further, PI3K activation (via PTEN inhibition by BPV) restored neuroinflammation and depressive-like behavior, accompanied by altered synaptic protein and spine numbers in G-2C mice in the presence of LPS. In addition, NF-κB and JNK inhibitor (BAY, SP600125) treatments reversed the effects of BPV. Moreover, these results were further validated with an NR2C antagonist DQP-1105. Collectively, these observations support the astrocytic-NR2C contribution to LPS-induced neuroinflammation, depression, and synaptic deficits.

Stress, pain, anxiety, and depression in endometriosis-Targeting glial activation and inflammation.

Endometriosis (EM) is a gynecological inflammatory disease often accompanied by stress, chronic pelvic pain (CPP), anxiety, and depression, leading to a diminished quality of life. This review aims to discuss the relationship between systemic and local inflammatory responses in the central nervous system (CNS), focusing on glial dysfunctions (astrocytes and microglia) as in critical brain regions involved in emotion, cognition, pain processing, anxiety, and depression. The review presents that EM is connected to increased levels of pro-inflammatory cytokines in the circulation. Additionally, chronic stress and CPP as stressors may contribute to the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, depleting the production of inflammatory mediators in the circulatory system and the brain. The systemic cytokines cause blood-brain barrier (BBB) breakdown, activate microglia in the brain, and lead to neuroinflammation. Furthermore, CPP may induce neuronal morphological alterations in critical regions through central sensitization and the activation of glial cells. The activation of glial cells, particularly the polarization of microglia, leads to the activation of the NLRP3 inflammasome and the overproduction of inflammatory cytokines. These inflammatory cytokines interact with the signaling pathways involved in neural plasticity. Additionally, persistent inflammatory conditions in the brain lead to neuronal death, which is correlated with a reduced volume of key brain regions such as the hippocampus. This review highlights the involvement of glial cells in the pathogenesis of the mental comorbidities of EM (i.e., pain, anxiety, and depression) and to discuss potential therapeutic approaches for targeting the inflammation and activation of microglia in key brain regions.

Long-Term Immunomodulatory Impact of VNS on Peripheral Cytokine Profiles and Its Relationship with Clinical Response in Difficult-to-Treat Depression (DTD).

Vagus nerve stimulation (VNS) represents a long-term adjunctive treatment option in patients with difficult-to-treat depression (DTD). Anti-inflammatory effects have been discussed as a key mechanism of action of VNS. However, long-term investigations in real-world patients are sparse. In this naturalistic observational study, we collected data on cytokines in peripheral blood in n = 6 patients (mean age 47.8) with DTD and VNS treatment at baseline and at 6 months follow-up. We have identified clusters of peripheral cytokines with a similar dynamic over the course of these 6 months using hierarchical clustering. We have investigated cytokine changes from baseline to 6 months as well as the relationship between the cytokine profile at 6 months and long-term response at 12 months. After 6 months of VNS, we observed significant correlations between cytokines (p < 0.05) within the identified three cytokine-pairs which were not present at baseline: IL(interleukin)-6 and IL-8; IL-1ß and TNF-α; IFN-α2 and IL-33. At 6 months, the levels of all the cytokines of interest had decreased (increased in non-responders) and were lower (5-534 fold) in responders to VNS than in non-responders: however, these results were not statistically significant. VNS-associated immunomodulation might play a role in long-term clinical response to VNS.

Depressive-like Behavior Is Accompanied by Prefrontal Cortical Innate Immune Fatigue and Dendritic Spine Losses after HIV-1 Tat and Morphine Exposure.

Opioid use disorder (OUD) and HIV are comorbid epidemics that can increase depression. HIV and the viral protein Tat can directly induce neuronal injury within reward and emotionality brain circuitry, including the prefrontal cortex (PFC). Such damage involves both excitotoxic mechanisms and more indirect pathways through neuroinflammation, both of which can be worsened by opioid co-exposure. To assess whether excitotoxicity and/or neuroinflammation might drive depressive behaviors in persons infected with HIV (PWH) and those who use opioids, male mice were exposed to HIV-1 Tat for eight weeks, given escalating doses of morphine during the last two weeks, and assessed for depressive-like behavior. Tat expression decreased sucrose consumption and adaptability, whereas morphine administration increased chow consumption and exacerbated Tat-induced decreases in nesting and burrowing-activities associated with well-being. Across all treatment groups, depressive-like behavior correlated with increased proinflammatory cytokines in the PFC. Nevertheless, supporting the theory that innate immune responses adapt to chronic Tat exposure, most proinflammatory cytokines were unaffected by Tat or morphine. Further, Tat increased PFC levels of the anti-inflammatory cytokine IL-10, which were exacerbated by morphine administration. Tat, but not morphine, decreased dendritic spine density on layer V pyramidal neurons in the anterior cingulate. Together, our findings suggest that HIV-1 Tat and morphine differentially induce depressive-like behaviors associated with increased neuroinflammation, synaptic losses, and immune fatigue within the PFC.

Depressive symptoms predict antibody titers after a second dose of the SARS-CoV-2 BNT162b2 vaccine among hospital workers in Japan.

BACKGROUND: Although factors associated with the antibody response to the BNT162b2 mRNA COVID-19 vaccine have been reported, psychological factors have not been examined. Depression or anxiety may affect vaccine reactions because these factors influence immune responses. This study aimed to determine whether psychological status at the time of vaccination predicts antibody responses. METHODS: A prospective observational study of the BNT162b2 mRNA COVID-19 vaccine response was carried out among individuals attending for an annual health check-up. Participants included 78 volunteers out of 80 hospital workers in Nagoya, Japan. No participants had been infected with COVID-19 and all gave written informed consent to participate in the study. Blood samples were obtained approximately 28 days after the second dose of the vaccine, and antibody titers of the SARS-CoV-2 spike protein were determined using the SARS-CoV-2 IgG II Quant assay. Participants completed the Japanese version of the hospital anxiety and depression scale (HADS) questionnaire, one day before both vaccinations. Participants also recorded any adverse reactions, such as body temperature and other side effects, every day for two weeks after each dose. The relationships between antibody titers and the predictive factors were analyzed using multiple linear regression analysis, with the antibody titers as the dependent variables, followed by univariate analysis. RESULTS: Multiple linear regression analysis revealed that no or excessive alcohol intake (p = 0.039), poor results from a health check-up (p = 0.011), a longer duration between the second dose and blood collection (p = 0.039), and increased degree of depressive symptoms (p = 0.041) were significant negative predictors of antibody titers, while body temperature one day after the second dose as a significant positive predictor of antibody titers (p < 0.0005). CONCLUSION: We identified that depressive symptoms just before the second dose of the BNT162b2 mRNA COVID-19 were an independent negative predictor of antibody responses, in addition to other factors. Our results highlight the importance of mental health at the time of vaccination to achieve the higher antibody responses necessary to acquire humoral immunity.

Changes in fecal microbiota composition and the cytokine expression profile in school-aged children with depression: A case-control study.

Depression in childhood negatively affects the growth and development, school performance, and peer or family relationships of affected children, and may even lead to suicide. Despite this, its etiology and pathophysiology remain largely unknown. Increasing evidence supports that gut microbiota plays a vital role in the development of childhood depression. However, little is known about the underlying mechanisms, as most clinical studies investigating the link between gut microbiota and depression have been undertaken in adult cohorts. In present study, a total of 140 school-aged children (6-12 years) were enrolled, including 92 with depression (male/female: 42/50) and 48 healthy controls (male/female: 22/26) from Lishui, Zhejiang, China. Illumina sequencing of the V3-V4 region of the 16S rRNA gene was used to investigate gut microbiota profiles while Bio-Plex Pro Human Cytokine 27-plex Panel was employed to explore host immune response. We found that, compared with healthy controls, children with depression had greater bacterial richness and altered ß-diversity. Pro-inflammatory genera such as Streptococcus were enriched in the depression group, whereas anti-inflammatory genera such as Faecalibacterium were reduced, as determined by linear discriminant analysis effect size. These changes corresponded to altered bacterial functions, especially the production of immunomodulatory metabolites. We also identified the presence of a complex inflammatory condition in children with depression, characterized by increased levels of pro-inflammatory cytokines such as IL-17 and decreased levels of anti-inflammatory cytokines such as IFN-γ. Correlation analysis demonstrated that the differential cytokine abundance was closely linked to changes in gut microbiota of children with depression. In summary, key functional genera, such as Streptococcus and Faecalibacterium, alone or in combination, could serve as novel and powerful non-invasive biomarkers to distinguish between children with depression from healthy ones. This study was the first to demonstrate that, in Chinese children with depression, gut microbiota homeostasis is disrupted, concomitant with the activation of a complex pro-inflammatory response. These findings suggest that gut microbiota might play an important role in the pathogenesis of depression in school-aged children, while key functional bacteria in gut may serve as novel targets for non-invasive diagnosis and patient-tailored early precise intervention in children with depression.

Childhood trauma and LPS-stimulated inflammation in adulthood: Results from the Netherlands Study of Depression and Anxiety

BACKGROUND: Childhood trauma (CT) is robustly associated with psychiatric disorders including major depressive and anxiety disorders across the life span. The innate immune system may play a role in the relation between CT and stress-related psychopathology. However, whether CT influences the innate production capacity of cytokine levels following ex vivo stimulation by lipopolysaccharide (LPS), is currently unknown. METHODS: Using data from the Netherlands Study of Depression and Anxiety (NESDA, n=1237), we examined whether CT (emotional neglect, emotional, physical, and sexual abuse before the age of 16), assessed by the Childhood Trauma Interview, was associated with levels in supernatants of interferon (IFN)γ, interleukin-2 (IL-2), IL-4, IL-6, IL-8, IL-10, IL-18, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1α, MIP-1ß, matrix metalloproteinase-2 (MMP-2), TNFα and TNFß after ex vivo stimulation with LPS. Cytokines were analysed individually and cumulatively (overall inflammation index and number of cytokines in high-risk quartile (HRQ)) using linear regression analyses. RESULTS: After adjustment for demographic, lifestyle, and health-related covariates, total CT severity was associated with the overall inflammation index (ß = 0.085, PFDR = 0.011), the number of cytokines in HRQ (ß = 0.063, PFDR = 0.036), and individual markers of IL-2 (ß = 0.067, PFDR = 0.036), IL-6 (ß = 0.091 PFDR = 0.011), IL-8 (ß = 0.085 PFDR = 0.011), IL-10 (ß = 0.094 PFDR = 0.011), MCP-1 (ß = 0.081 PFDR = 0.011), MIP-1α (ß = 0.061 PFDR = 0.047), MIP1-ß (ß = 0.077 PFDR = 0.016), MMP-2 (ß = 0.070 PFDR = 0.027), and TNFß (ß = 0.078 PFDR = 0.016). Associations were strongest for individuals with severe CT, reporting multiple types or higher frequencies of trauma. Half of the findings persisted after adjustment for psychiatric status. The findings were consistent across different CT types. CONCLUSION: Childhood Trauma is associated with increased LPS-stimulated cytokine levels, with evidence for a dose-response relationship. Our results highlight a dysregulated innate immune system capacity in adults with CT, which could contribute to an increased vulnerability for psychopathology and somatic disorders across the lifespan.

Associations between Autoimmunity and Depression: Serum IL-6 and IL-17 Have Directly Impact on the HAMD Scores in Patients with First-Episode Depressive Disorder.

Objective: The study is aimed at evaluating the immune-activation state before and after treatment in patients with first-episode depressive disorder (FDD) with evaluating the ILs and CRP levels and further clarifying the association between autoimmunity and the etiology and pathogenesis of FDD. Methods: We designed a case-control study. FDD patients and healthy subjects were enrolled in the FDD group and control group. Serum IL-6, IL-17, and CRP were measured before and after selective serotonin reuptake inhibitor (SSRI) therapy, as well as Hamilton rating scale for depression (HAMD) and life event scale (LES) scores. The correlations between IL-6 and IL-17 and HAMD and LES scores were analysed, and multiple linear regression analysis was performed for HAMD score. Results: 40 FDD patients and 40 healthy subjects were included in the FDD and control group from October 2009 to September 2012. Before treatment, the IL-6 (28.99 ± 5.51, P < 0.001) and IL-17 (41.15 ± 4.80, P < 0.001) in the FDD group were significantly higher than the control group (16.84 ± 3.78 and 21.68 ± 3.72, respectively). The C-reactive protein (CRP) level in two groups was comparable (P = 0.879). After treatment, the IL-6 (18.69 ± 5.07, P < 0.001) and IL-17 (30.67 ± 3.47, P < 0.001) levels and HAMD scores (6.73 ± 4.15) in the FDD group were significantly decreased than before treatment (P < 0.001, respectively). CRP level was slightly increased after treatment without statistically significant (P = 0.239). The HAMD score correlated with IL-6 (r = 0.638, P < 0.001) and IL-17 (r = 0.927, P < 0.001); the total LES and negative LES also correlated with IL-6 (r = 0.226, P < 0.05) (r = 0.366, P <0.001) and IL-17 (r = 0.348, P < 0.001) (r = 0.493, P < 0.001). Multiple linear regression analysis showed that both of the IL-6 and IL-17 had direct impact on HAMD score. Conclusion: The autoimmunity status was overactivated in FDD patients, and serum IL-6 and IL-17 levels had direct impact on the HAMD score. Patients who experienced more negative life events had higher activation level of autoimmunity status and HAMD scores, and serum IL-6 and IL-17 levels can be decreased by SSRI treatment.

Innate immune stimulation by monophosphoryl lipid A prevents chronic social defeat stress-induced anxiety-like behaviors in mice.

BACKGROUND: Innate immune pre-stimulation can prevent the development of depression-like behaviors in chronically stressed mice; however, whether the same stimulation prevents the development of anxiety-like behaviors in animals remains unclear. We addressed this issue using monophosphoryl lipid A (MPL), a derivative of lipopolysaccharide (LPS) that lacks undesirable properties of LPS but still keeps immune-enhancing activities. METHODS: The experimental mice were pre-injected intraperitoneally with MPL before stress exposure. Depression was induced through chronic social defeat stress (CSDS). Behavioral tests were conducted to identify anxiety-like behaviors. Real-time polymerase chain reaction (PCR) and biochemical assays were employed to examine the gene and protein expression levels of pro-inflammatory markers. RESULTS: A single MPL injection at the dose of 400 and 800 µg/kg 1 day before stress exposure prevented CSDS-induced anxiety-like behaviors, and a single MPL injection (400 µg/kg) five but not 10 days before stress exposure produced similar effect. The preventive effect of MPL on anxiety-like behaviors was also observed in CSDS mice who received a second MPL injection 10 days after the first MPL injection or a 4 × MPL injection 10 days before stress exposure. MPL pre-injection also prevented the production of pro-inflammatory cytokines in the hippocampus and medial prefrontal cortex in CSDS mice, and inhibiting the central immune response by minocycline pretreatment abrogated the preventive effect of MPL on CSDS-induced anxiety-like behaviors and pro-inflammatory cytokine productions in the brain. CONCLUSIONS: Pre-stimulation of the innate immune system by MPL can prevent chronic stress-induced anxiety-like behaviors and neuroinflammatory responses in the brain in mice.

Phytoestrogen genistein modulates neuron-microglia signaling in a mouse model of chronic social defeat stress.

Microglia, resident immune cells in the brain, are shown to mediate the crosstalk between psychological stress and depression. Interestingly, increasing evidence indicates that sex hormones, particularly estrogen, are involved in the regulation of immune system. In this study, we aimed to understand the potential effects of chronic social defeat stress (CSDS) and genistein (GEN), an estrogenic compound of the plant origin, on neuron-microglia interactions in the mouse hippocampus. The time spent in the avoidance zone in the social interaction test was increased by CSDS 1 day after the exposure, while the avoidance behavior returned to control levels 14 days after the CSDS exposure. Similar results were obtained from the elevated plus-maze test. However, the immobility time in the forced swim test was increased by CSDS 14 days after the exposure, and the depression-related behavior was in part alleviated by GEN. The numerical densities of microglia in the hippocampus were increased by CSDS, and they were decreased by GEN. The voxel densities of synaptic structures and synaptic puncta colocalized with microglia were decreased by CSDS, and they were increased by GEN. Neither CSDS nor GEN affected the gene expressions of major pro-inflammatory cytokines. Conversely, the expression levels of genes related to neurotrophic factors were decreased by CSDS, and they were partially reversed by GEN. These findings show that GEN may in part alleviate stress-related symptoms, and the effects of GEN may be associated with the modulation of neuron-microglia signaling via chemokines and neurotrophic factors in the hippocampus.

Multifaceted interconnections between macrophage migration inhibitory factor and psychiatric disorders.

Inflammation is involved in the pathogenesis of psychiatric disorders. Many previous studies have defined the important roles of inflammatory factors in the pathogenesis, diagnosis, and treatment outcomes of psychiatric disorders. Macrophage migration inhibitory factor (MIF), a pro-inflammatory factor, has been gradually recognized to be involved in the development of neurological diseases in recent years. Our current review focuses on discussing the potential beneficial and detrimental roles of MIF in psychiatric disorders. We will provide new mechanistic insights for the development of potential diagnostic and therapeutic biomarkers based on MIF for psychiatric diseases.

Natural products for the treatment of stress-induced depression: Pharmacology, mechanism and traditional use.

ETHNOPHARMACOLOGICAL RELEVANCE: Depression, one of the most common psychiatric disorders, is the fourth leading cause of long-term disability worldwide. A series of causes triggered depression, including psychological stress and conflict, as well as biological derangement, among which stress has a pivotal role in the development of depression. Traditional herbal medicine has been used for the treatment of various disorders including depression for a long history with multi-targets, multi-levels and multi-ways, attracting great attention from scholars. Recently, natural products have been commercialized as antidepressants which have become increasingly popular in the world health drug markets. Major research contributions in ethnopharmacology have generated and updated vast amount of data associated with natural products in antidepressant-like activity. AIMS OF THE REVIEW: This review aims to briefly discuss the pathological mechanism, animal models of stress-induced depression, traditional use of herbal medicines and especially recapitulate the natural products with antidepressant activity and their pharmacological functions and mechanism of action, which may contribute to a better understanding of potential therapeutic effects of natural products and the development of promising drugs with high efficacy and low toxicity for the treatment of stress-induced depression. MATERIALS AND METHODS: The contents of this review were sourced from electronic databases including PubMed, Sci Finder, Web of Science, Science Direct, Elsevier, Google Scholar, Chinese Knowledge On frastructure (CNKI), Wan Fang, Chinese Scientific and Technological Periodical Database (VIP) and Chinese Biomedical Database (CBM). Additional information was collected from Yao Zhi website (https://db.yaozh.com/). Data were obtained from April 1992 to June 2021. Only English language was applied to the search. The search terms were 'stress-induced depression', 'pathological mechanism' in the title and 'stress', 'depression', 'animal model' and 'natural products' in the whole text. RESULTS: Stress-induced depression is related to the monoaminergic system, hypothalamic-pituitary-adrenal (HPA) axis, neuronal plasticity and a series of inflammatory factors. Four main types of animal models of stress-induced depression were represented. Fifty-eight bioactive phytochemical compounds, fifty-six herb medicines and five formulas from traditional Chinese medicine were highlighted, which exert antidepressant effects by inhibiting monoamine oxidase (MAO) reaction, alleviating dysfunction of the HPA axis and nerve injury, and possessing anti-inflammatory activities. CONCLUSIONS: Natural products provide a large number of compounds with antidepressant-like effects, and their therapeutic impacts has been highlighted for a long time. This review summarized the pathological mechanism and animal models of stress-induced depression, and the natural products with antidepressant activity in particular, which will shed light on the action mechanism and clinical potential of these compounds. Natural products also have been a vital and promising source for future antidepressant drug discovery.

Links Between Inflammation, Mood, and Physical Function Among Older Adults With HIV.

OBJECTIVES: People living with human immunodeficiency virus (PLWH) treated with antiretrovirals have life spans similar to their HIV-negative peers. Yet, they experience elevated inflammation-related multimorbidity. Drawing on biopsychosocial determinants of health may inform interventions, but these links are understudied in older PLWH. We investigated cross-sectional relationships between psychosocial factors (mood, loneliness, and stigma), inflammatory markers, and age-related health outcomes among 143 PLWH aged 54-78 years. METHOD: Participants provided blood samples for serum cytokine and C-reactive protein (CRP) analyses, completed surveys assessing psychosocial factors and health, and completed frailty assessments. Regression models tested relationships between key psychosocial-, inflammation, and age-related health variables, adjusting for relevant sociodemographic and clinical factors. RESULTS: Participants with more depressive symptoms had higher composite cytokine levels than those with fewer depressive symptoms (ß = 0.22, t(126) = 2.71, p = .008). Those with higher cytokine levels were more likely to be prefrail or frail (adjusted odds ratio = 1.72, 95% confidence interval = 1.01-2.93) and reported worse physical function (ß = -0.23, t(129) = -2.64, p = .009) and more cognitive complaints (ß = -0.20, t(129) = -2.16, p = .03) than those with lower cytokine levels. CRP was not significantly related to these outcomes; 6-month fall history was not significantly related to inflammatory markers. DISCUSSION: Novel approaches are needed to manage comorbidities and maximize quality of life among older PLWH. Illustrating key expected biopsychosocial links, our findings highlight several factors (e.g., depressive symptoms, poorer physical function) that may share bidirectional relationships with chronic inflammation, a key factor driving morbidity. These links may be leveraged to modify factors that drive excessive health risk among older PLWH.

Chemokine profile in women with moderate to severe anxiety and depression during pregnancy.

BACKGROUND: Cytokine levels have been extensively described in pregnant subjects under normal and pathological conditions, including mood-related disorders. Concerning chemokines, very few studies have reported their association with psychiatric disorders during pregnancy. Therefore, we explored the chemokine profile in women exhibiting anxiety and depression during late pregnancy in the present study. METHODS: One hundred twenty-six pregnant women in the 3rd trimester of pregnancy, displaying moderate to severe anxiety (ANX) alone and women exhibiting moderate to severe anxiety with comorbid depression (ANX + DEP), and 40 control pregnant women without affective disorders (CTRL) were evaluated through the Hamilton Anxiety Rating Scale (HARS) and the Hamilton Depression Rating Scale (HDRS). Serum chemokine levels of MCP-1 (CCL2), RANTES (CCL5), IP-10 (CXCL10), Eotaxin (CCL11), TARC (CCL17), MIP-1α (CCL3), MIP-1ß (CCL4), MIG (CXCL9), MIP-3α (CCL20), ENA-78 (CXCL5), GROα (CXCL1), I-TAC (CXCL11) and IL-8 (CXCL8)] were measured by immunoassay. Clinical, biochemical, and sociodemographic parameters were correlated with HARS and HDRS score values. RESULTS: Serum levels of most chemokines were significantly higher in the ANX and in the ANX + DEP groups, when compared to the CTRL group. Positive correlations were observed between MIP-1α/CCL3, MIP-1ß/CCL4, MCP-1/CCL2, MIP-3α/CCL20, RANTES/CCL5, Eotaxin/CCL11, and I-TAC/CXCL11 with high scores for anxiety (HARS) (p < 0.05) and for depression (HDRS) (p < 0.004). After controlling clinical measures for age + gwk + BMI, chemokines such as IL-8/CXCL8, MCP-1/CCL2 and MIP-1ß/CCL4 were found associated with high scores for anxiety (p < 0.05) in the ANX group. TARC/CCL17 and Eotaxin/CCL11 showed significant associations with high scores for depression (p < 0.04) whereas, MCP-1/CCL2 and MIP-1α/CCL3 were significantly associated with high scores for anxiety (p < 0.05) in the ANX + DEP group. Using a multivariate linear model, high serum levels of MIP-1ß/CCL4 and Eotaxin/CCL11 remained associated with depression (p < 0.01), while, IL-8/CXCL8, MIP-1ß/CCL4, MCP-1/CCL2, and MIP-1α/CCL3 were associated with anxiety (p < 0.05) in the symptomatic groups. CONCLUSIONS: Our data show that serum levels of distinct chemokines are increased in women exhibiting high levels of affective symptoms during late pregnancy. Our results suggest that increased levels of anxiety, depressive symptoms, and mood-related disorders may promote changes in specific functional chemokines associated with a chronic inflammatory process. If not controlled, it may lead to adverse obstetric and negative neonate outcomes, child development and neuropsychiatric alterations in the postnatal life. HIGHLIGHTS: Chemokine levels increase in affective disorders during pregnancy.

Links Between Gut Dysbiosis and Neurotransmitter Disturbance in Chronic Restraint Stress-Induced Depressive Behaviours: the Role of Inflammation.

Accumulating evidence has shown that inflammation, the gut microbiota, and neurotransmitters are closely associated with the pathophysiology of depression. However, the links between the gut microbiota and neurotransmitter metabolism remain poorly understood. The present study aimed to investigate the neuroinflammatory reactions in chronic restraint stress (CRS)-induced depression and to delineate the potential links between the gut microbiota and neurotransmitter metabolism. C57BL/6 mice were subjected to chronic restraint stress for 5 weeks, followed by behavioural tests (the sucrose preference test, forced swim test, open field test, and elevated plus maze) and analysis. The results showed that CRS significantly increased interleukin-1 beta (IL-1ß), interleukin-2 (IL-2), interleukin-6 (IL-6), and tumour necrosis factor α (TNFα) levels and decreased brain-derived neurotrophic factor (BDNF) expression, accompanied by the activation of IkappaB-alpha-phosphorylation-nuclear factor kappa-B (IκBα-p-NF-κB) signalling in the mouse hippocampus. In addition, the neurotransmitter metabolomics results showed that CRS resulted in decreased levels of plasma 5-hydroxytryptamine (5-HT), dopamine (DA), and noradrenaline (NE) and their corresponding metabolites, and gut microbiota faecal metabolites with the 16S rRNA gene sequencing indicated that CRS caused marked microbiota dysbiosis in mice, with a significant increase in Helicobacter, Lactobacillus, and Oscillibacter and a decrease in Parabacteroides, Ruminococcus, and Prevotella. Notably, CRS-induced depressive behaviours and the disturbance of neurotransmitter metabolism and microbiota dysbiosis can be substantially restored by dexamethasone (DXMS) administration. Furthermore, a Pearson heatmap focusing on correlations between the microbiota, behaviours, and neurotransmitters showed that Helicobacter, Lactobacillus, and Oscillibacter were positively correlated with depressive behaviours but were negatively correlated with neurotransmitter metabolism, and Parabacteroides and Ruminococcus were negatively correlated with depressive behaviours but were positively correlated with neurotransmitter metabolism. Taken together, the results suggest that inflammation is involved in microbiota dysbiosis and the disturbance of neurotransmitter metabolism in CRS-induced depressive changes, and the delineation of the potential links between the microbiota and neurotransmitter metabolism will provide novel strategies for depression treatment.

Scutellarin alleviates depression-like behaviors induced by LPS in mice partially through inhibition of astrocyte-mediated neuroinflammation.

Depression is a kind of common mental disorder associated with neuroinflammation, and astrocytes play a vital role in regulating and mediating neuroinflammation in central nervous system. Scutellarin has significant anti-inflammatory and neuroprotective effects. However, whether scutellarin exerts antidepressant effect remains unknown. In present study, it was found that scutellarin suppressed LPS-induced neuroinflammation in the hippocampus and alleviated depression-like behaviors in mice. In addition, scutellarin inhibited LPS-induced elevation of TNFα, IL-1ß, IL-6 and iNOS, and reversed the downregulation of IL-4 and BDNF in astrocytes in vitro. Furthermore, the activated TLR4/NF-κB pathway in LPS-treated astrocytes was suppressed by scutellarin. Collectively, these results suggest that scutellarin ameliorates depression-like behaviors induced by neuroinflammation partially through inhibiting the TLR4/NF-κB pathway in astrocytes.

Exploring Molecular Mechanisms Involved in the Development of the Depression-Like Phenotype in Interleukin-18-Deficient Mice.

Interleukin-18 (IL-18) is an inflammatory cytokine that has been linked to energy homeostasis and psychiatric symptoms such as depression and cognitive impairment. We previously revealed that deficiency in IL-18 led to hippocampal abnormalities and resulted in depression-like symptoms. However, the impact of IL-18 deficiency on other brain regions remains to be clarified. In this study, we first sought to confirm that IL-18 expression in neural cells can be found in human brain tissue. Subsequently, we examined the expression of genes in the prefrontal cortex of Il18 -/- mice and compared it with gene expression in mice subjected to a chronic mild stress model of depression. Extracted genes were further analyzed using Ingenuity® Pathway Analysis, in which 18 genes common to both the chronic mild stressed model and Il18 -/- mice were identified. Of those, 16 were significantly differentially expressed between Il18+/+ and Il18 -/- mice. We additionally measured protein expression of α-2-HS-glycoprotein (AHSG) and transthyretin (TTR) in serum and the brain. In the prefrontal cortex of Il18 -/- mice, TTR but not AHSG was significantly decreased. Conversely, in the serum of Il18 -/- mice, AHSG was significantly increased but not TTR. Therefore, our results suggest that in IL-18-deficit conditions, TTR in the brain is one of the mediators causally related to depression, and AHSG in peripheral organs is one of the regulators inducing energy imbalance. Moreover, this study suggests a possible "signpost" to clarify the molecular mechanisms commonly underlying the immune system, energy metabolism, neural function, and depressive disorders.

Innate immunity receptors in depression and suicide: upregulated NOD-like receptors containing pyrin (NLRPs) and hyperactive inflammasomes in the postmortem brains of people who were depressed and died by suicide.

BACKGROUND: Abnormalities of inflammation have been implicated in the pathophysiology of depression and suicide, based on observations of increased levels of proinflammatory cytokines in the serum of people who were depressed and died by suicide. More recently, abnormalities in cytokines and innate immunity receptors such as toll-like receptors have also been observed in the postmortem brains of people who were depressed and died by suicide. In addition to toll-like receptors, another subfamily of innate immunity receptors known as NOD-like receptors containing pyrin (NLRPs) are the most widely present NOD-like receptors in the central nervous system. NLRPs also form inflammasomes that play an important role in brain function. We studied the role of NLRPs in depression and suicide. METHODS: We determined the protein and mRNA expression of NLRP1, NLRP3 and NLRP6 and the components of their inflammasomes (i.e., adaptor molecule apoptosis-associated speck-like protein [ASC], caspase1, caspase3, interleukin [IL]-1ß and IL-18) postmortem in the prefrontal cortex of people who were depressed and died by suicide, and in healthy controls. We determined mRNA levels using quantitative polymerase chain reaction, and we determined protein expression using Western blot immunolabelling. RESULTS: We found that the protein and mRNA expression levels of NLRP1, NLRP3, NLRP6, caspase3 and ASC were significantly increased in people who were depressed and died by suicide compared to healthy controls. LIMITATIONS: Some people who were depressed and died by suicide were taking antidepressant medication at the time of their death. CONCLUSION: Similar to toll-like receptors, NLRP and its inflammasomes were upregulated in people who were depressed and died by suicide compared to healthy controls. Innate immunity receptors in general - and NLRPs and inflammasomes in particular - may play an important role in the pathophysiology of depression and suicide.