To analyze the symptoms, courses, and severities of depressive disorder, as well as the morphological changes in the spleens and related immune mechanisms, we recruited patients with first-episode or recurrent major depressive disorder (MDD) (patient group) and healthy controls (normal group) matched in age and gender. We measured their plasma MICB (pg/ml), ULBP1 (ng/ml), and splenic volume (cm3) at baseline. The patient group was randomly assigned to receive (S)-ketamine (study group) or saline (control group), and the above indices were collected again on the 4th weekend after administration. At baseline, both MICB and splenic volume were significantly higher in the patient group than in the normal group. A positive correlation was observed between MICB and splenic volume in the patient group. After (S)-ketamine administration, the elevated splenic volume and MICB levels decreased. These results suggest that the pathogenesis of MDD may involve abnormal MICB expression and splenic morphology. (S)-ketamine may ameliorate inflammation and enhance splenic function, thereby relieving MDD symptoms.

Interleukin 18 (IL-18) is a pleiotropic cytokine that regulates peripheral innate and adaptive immune response and is also expressed in the brain. Here, we summarize the current knowledge on the biology of IL-18 in the brain and the efforts to determine its significance concerning neurological and psychiatric conditions. The picture that emerges is that of a heavily regulated molecule that can contribute to neuroinflammatory-mediated neuronal survival but can also serve as a neuromodulator that affects behaviour. We also summarize evidence showing how the brain can control the synthesis of peripheral IL-18 during stress by hormonal and neuronal signalling, regulating tissue-specific promoter usage. We discuss how this may represent one of the mechanisms by which the brain affects immune functions and what its implications are when considering IL-18 as a biomarker of psychiatric conditions.

Patent foramen ovale (PFO), a cardiac anatomical anomaly inducing abnormal haemodynamics, leads to a paradoxical bypass of the pulmonary circulation. PFO closure might alleviate migraines; however, clinical evidence and basic experiments for the relationship are lacking. To explore the effect of PFO on migraine, 371 migraineurs finishing blood tests and contrast transthoracic echocardiography for the detection of PFO were prospectively included. Multivariate regression analysis revealed that PFO was independently associated with aura, and lower cystatin-C (cys-C) and calcium levels. Among them, patients with PFO who underwent percutaneous PFO closure were continuously followed up 1 year after the operation. The intensity of migraine was significantly relieved and the levels of cys-C and calcium increased after PFO closure. Untargeted and targeted metabolomics of plasma from migraineurs before and after PFO closure revealed that 5-HT and glutathione (GSH) metabolites were differentially expressed after PFO closure. The differential metabolites were then validated in the plasma and brain tissues of PFO mouse models by LC-MS/MS analysis. Desorption electrospray ionization mass imaging demonstrated that these metabolic alterations occurred mainly in the posterior cerebral cortex. Collectively, aura, cys-C and calcium could be biomarkers of migraineurs with PFO. PFO might have an impact on the posterior head associated with the regulation of 5-HT and GSH. PFO closure might relieve migraine by improving 5-HT clearance metabolism and ameliorating redox reactions. Our results may provide evidence for an indication of PFO closure in migraine and support the related potential mechanism. KEY POINTS: Aura, and levels of cystatin-C and calcium are biomarkers of migraineurs with a patent foramen ovale (PFO). The clearance of pulmonary metabolism of 5-HT and deoxygenated blood might be the reason for the improvement of migraine symptoms in patients with PFO. The posterior region of the brain is the main area responsible for PFO-induced migraine.

To study clinical and immunological relationships in patients with early schizophrenia during remission.

Forty-eight patients (53% females and 47% males) were examined at the initial stage of schizophrenia during remission (age 28.3±5.8 years). The duration of the disease was 2.7±1.3 years. The control group consisted of healthy males and females aged 18 to 30 years. The study used clinical-psychopathological and laboratory methods, as well as scale assessment.

In patients with early schizophrenia in remission, in 70% of cases, there was an increase in blood levels of cytokines IL-6, IL-9, IL-10, IL-13, IL-22, TNF-α, CCL20/MIP3α (p<0.001) compared to the control group. Levels of IL-4 (r=0.45; p=0.023) and IL-9 (r=0.48; p=0.014) correlated with disease duration. The PANSS composite index correlated with IL-6 levels (r=0.46; p=0.022). Levels of several pro-inflammatory blood cytokines were significantly higher in patients treated with first-generation antipsychotics compared with patients treated with second-generation antipsychotics (p<0.001).

Changes in the concentrations of pro-inflammatory and anti-inflammatory interleukins, which are involved in the development of a nonspecific immune response as part of the systemic inflammatory response in patients with early schizophrenia during remission, have been demonstrated. The results suggest that in patients with the first episode of schizophrenia, the activation of immune inflammation plays a significant role in the development of the disease. Over time, such activation may stabilize and is associated with a greater severity of psychopathological symptoms.

The pathogenesis of cognitive impairment in schizophrenia (SCZ) remains unclear. Accumulating studies showed that inflammatory-immune dysregulation and altered brain derived neurotrophic factor (BDNF) levels play a crucial role in the psychopathology of SCZ. However, their association with cognitive dysfunction in first-episode SCZ patients has not been thoroughly investigated.

To explore the interaction effects between cognitive function and inflammatory cytokines and BDNF in first-episode SCZ.

The current study is a cross-sectional case-control investigation that recruited 84 patients with first-episode SCZ (SCZ group) and 80 healthy controls (HCs group) at the Huzhou Third Municipal Hospital between August 2021 and September 2023. ELISA was employed to measure the serum levels of interleukin (IL)-1β, IL-4, IL-6, IL-10, and BDNF. The Chinese brief cognitive test (C-BCT) and the positive and negative syndrome scales were measured the severity of cognitive impairment and psychiatric symptoms.

Compared to the HC group, the SCZ group exhibited elevated IL-1β and IL-6 levels, decreased BDNF levels, and reduced C-BCT scores (all P < 0.001). In SCZ, BDNF was negatively correlated with IL-6 (r = -0.324, P < 0.05). Information processing speed was negatively correlated with IL-6 (r = -0.315, P < 0.05) and positively with BDNF (r = 0.290, P < 0.05); attention, working memory, comprehensive ability, and executive function were negatively correlated with IL-1β and IL-6 (all P < 0.05) and positively with BDNF (all P < 0.05). Multiple regression analysis showed IL-6 influenced C-BCT dimensions (β = -0.218 to -0.327, all P < 0.05); attention and executive ability were influenced by IL-1β (β = -0.199 to -0.261, all P < 0.05); comprehensive executive ability was influenced by BDNF (β = 0.209, P < 0.05).

Our findings suggested that interrelationships between immune dysfunction and neurotrophic deficiency might underlie the pathological mechanisms of cognitive impairments in first-episode SCZ patients.

Latinx immigrants are exposed to acculturative stressors as they adapt to the U.S. However, little is known about the impact of acculturative stressors and psychosocial resilience on physiological responses and health over time. The purpose of this study was to examine trajectories of physiological stress markers among Latinx adults over time and examine the influence of acculturative stressors and psychosocial resilience factors on these different trajectories.

A community-based, longitudinal study was conducted with adult Latinx immigrants in North Carolina (N = 391) over a two-year period. Self-reported measures of ten different types of acculturative stressors (e.g., occupational, family, healthcare, discrimination) and psychosocial resilience factors (individual resilience, coping, ethnic pride, familism, and social support) along with urine samples were taken at baseline and 12- and 24-month follow-up periods. Biomarkers of physiological stress (inflammatory cytokines interleukin-6 (IL-6), IL-8 and IL-18 and C-Reactive Protein (CRP)) were measured in urine. Multivariate latent class growth analysis, linear mixed models, and unadjusted bivariate analyses were conducted to address the study aims.

Participants were an average of 39 years of age (SD = 6.94) and mostly women (68.8%) and Spanish speakers (83%). Three latent classes of physiological stress marker trajectories were identified: resilient, rapidly increasing stress, and chronic elevated stress. These latent classes had significant differences in gender, race, coping styles, ethnic pride, and parental acculturative stressors.

The findings from this study identify specific types of acculturative stressors and psychosocial resilience factors that are important targets for health promotion and disease prevention programs for Latinx immigrants.

Psychotic and mood disorders are discussed as part of the same continuum. The potential role of immune dysregulation in defining their clinical presentations, however, remains unclear. Differences in TNF-α, IL-6 and TGF-β levels were investigated in 143 patients with schizophrenia (SCH = 63) and bipolar disorder (BD = 80), in remission. Cytokines were evaluated against the dimensional assessment of psychosis and affective symptoms using the schizo-bipolar scale, together with the severity of the same symptom domains measured by the brief psychiatric rating scale (BPRS). Lower TGF-β was associated with more lifetime episodes, family risk for psychosis, and more severe mood and psychotic symptoms in all patients. BPRS Affect symptoms domain correlated with lower TGF-β levels in BD, and higher TGF-β levels in SCH patients. Using moderated mediation analysis, TGF-β was a relevant predictor only in the setting of non-categorical symptom distribution, with familial risk for psychosis confirmed as a significant moderator. Severity of BPRS Affect symptoms domain was an independent predictor of inclination towards the psychosis spectrum. The underlying immune dysregulation may be shared by the disorders, rather than a unique characteristic of each, having significant implications for our understanding of the continuum vs. categorical approach to psychosis and mood disorders.

From the original studies investigating the effects of adrenal gland secretion to modern high-throughput multidimensional analyses, stress research has been a topic of scientific interest spanning just over a century.

The objective of this review was to provide historical context for influential discoveries, surprising findings, and preclinical models in stress-related neuroimmune research. Furthermore, we summarize this work and present a current understanding of the stress pathways and their effects on the immune system and behavior. We focus on recent work demonstrating stress-induced immune changes within the brain and highlight studies investigating stress effects on microglia. Lastly, we conclude with potential areas for future investigation concerning microglia heterogeneity, bone marrow niches, and sex differences.

Stress is a phenomenon that ties together not only the central and peripheral nervous system, but the immune system as well. The cumulative effects of stress can enhance or suppress immune function, based on the intensity and duration of the stressor. These stress-induced immune alterations are associated with neurobiological changes, including structural remodeling of neurons and decreased neurogenesis, and these contribute to the development of behavioral and cognitive deficits. As such, research in this field has revealed important insights into neuroimmune communication as well as molecular and cellular mediators of complex behaviors relevant to psychiatric disorders.

The search for new parameters for the prediction of type 2 diabetes mellitus (T2DM) or its harmful consequences remains an important field of study. Depending on the low-grade inflammatory nature of diabetes, we investigated three proteins in T2DM patients: 1-aminocyclopropane-1-carboxylate synthase (ACCS), granulocyte-colony-stimulating factor (G-CSF), and Sma Mothers Against Decapentaplegic homolog-4 (SMAD4). In brief, sixty T2DM and thirty healthy controls had their serum levels of ACCS, G-CSF, SMAD4, and insulin tested using the ELISA method. The insulin resistance (IR) parameter (HOMA2IR), beta-cell function percentage (HOMA2%B), and insulin sensitivity (HOMA2%S) were all determined by the Homeostasis Model Assessment-2 (HOMA2) calculator. The predictability of these protein levels was investigated by neural network (NN) analysis and was associated with measures of IR. Based on the results, ACCS, G-CSF, and SMAD4 increased significantly in the T2DM group compared with the controls. Their levels depend on IR status and inflammation. The multivariate GLM indicated the independence of the levels of these proteins on the covariates or drugs taken. The receiver operating characteristic area under the curve (AUC) for the prediction of T2DM using NN analysis is 0.902, with a sensitivity of 71.4% and a specificity of 93.8%. The network predicts T2DM well with predicted pseudoprobabilities over 0.5. The model's predictive capability (normalized importance) revealed that ACCS is the best model (100%) for the prediction of T2DM, followed by G-CSF (75.5%) and SMAD4 (69.6%). It can be concluded that ACCS, G-CSF, and SMAD4 are important proteins in T2DM prediction, and their increase is associated with the presence of inflammation.

Inflammation is associated with the pathophysiology of schizophrenia. The blood markers for systemic inflammation include neutrophil-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), lymphocyte-monocyte ratio (LMR), system inflammation response index (SIRI), and platelet-lymphocyte ratio (PLR). However, these inflammation markers and their relationships with clinical phenotypes among Han Chinese patients with first-episode adolescent-onset schizophrenia (AOS) is unclear. This investigation aimed to elucidate the impact of inflammation on Han Chinese AOS patients as well as the association of blood-based inflammation markers with clinical symptoms.

Altogether, 203 Han Chinese individuals participated in this study, 102 first-episode AOS patients and 101 healthy controls. The assessment of inflammatory indices was based on complete blood cell count. Furthermore, schizophrenia-related clinical symptoms were evaluated using the five-factor model of the Positive and Negative Syndrome Scale (PANSS).

In Han Chinese first-episode AOS patients, levels of SIRI, PLR, SII, and NLR were significantly increased (p < 0.001), while LMR decreased (p < 0.001) compared to healthy controls. Furthermore, multivariate logistic regression showed that LMR, NLR, SII, and SIRI (all p < 0.05) were independently associated with AOS. Moreover, Receiver operating characteristics assessment indicated that NLR, SIRI, LMR, and SII could effectively distinguish AOS patients from healthy controls. Their areas under the curves were 0.734, 0.701, 0.715, and 0.730 (all p < 0.001). In addition, Correlation analysis revealed that LMR was negatively correlated with the PANSS total, negative, and cognitive factor scores (all p < 0.05); NLR was positively correlated with the cognitive factor score (p < 0.01); SII was negatively correlated with the positive factor score and positively with the negative and cognitive factor scores (all p < 0.05); SIRI was positively correlated with the PANSS total and cognitive factor scores (all p < 0.01).

This research established the involvement of peripheral blood inflammatory markers (LMR, NLR, SII, and SIRI) with the clinical manifestations and pathophysiology of schizophrenia, and these can serve as screening tools or potential indices of the inflammatory state and AOS symptoms severity.

This research has suggested a link between major depressive disorder (MDD) and infertility, with interleukin-18 (IL-18) being proposed as a potential mediator due to its connections to both conditions. A Mendelian randomization (MR) approach was utilized in this study, which drew on genetic data from 500,199 European participants studied for MDD, along with additional IL-18 and reproductive health data from the FinnGen consortium and GWAS datasets. Single nucleotide polymorphisms were employed as instrumental variables to examine the causal relationships between MDD, genetically predicted IL-18 levels, and infertility. In our study, bidirectional MR analysis revealed a significant inverse causal relationship between MDD and genetically predicted IL-18 levels, with a higher genetic predisposition to MDD, correlating with reduced IL-18 levels (β: -0.40; 95% confidence interval (CI): -0.69 to -0.11; P = 7.09 × 10-3). Additionally, MDD is found to significantly increase the risk of female infertility. Notably, genetically predicted IL-18 levels demonstrated a protective effect against female infertility (odds ratio (OR): 0.92; 95% CI: 0.86-0.98; P = 1.17 × 10-2). Mediation analysis indicated that genetically predicted IL-18 levels partially mediated the impact of MDD on female infertility associated with cervical, vaginal, other or unspecified origin, accounting for up to 14.61% of this effect. No evidence of pleiotropy or heterogeneity was detected. The role of genetic predispositions to MDD in influencing genetically predicted IL-18 levels, and subsequently, female infertility, was highlighted by our study, offering insights into the complex interplay between mental health and reproductive biology. These findings contribute to a deeper understanding of the genetic and molecular pathways influencing these conditions, suggesting new directions for research and potential therapeutic interventions.

Schizophrenia (SCZ) imposes a significant burden on patients and their families because of its high prevalence rate and disabling nature. Given the lack of definitive conclusions regarding its pathogenesis, physicians heavily rely on patients' subjective symptom descriptions for diagnosis because reliable diagnostic biomarkers are currently unavailable. The role of the inflammatory response in the pathogenesis of SCZ has been supported by some studies. The findings of these studies showed abnormal changes in the levels of inflammatory factors, such as cytokines (CKs), in both peripheral blood and cerebrospinal fluid (CSF) among individuals affected by SCZ. The findings imply that inflammatory factors could potentially function as risk indicators for the onset of SCZ. Consequently, researchers have directed their attention towards investigating the potential utility of CKs as viable biomarkers for diagnosing SCZ. Extracellular vesicles (EVs) containing disease-specific components exhibit remarkable stability and abundance, making them promising candidates for biomarker discovery across various diseases. CKs encapsulated within EVs secreted by immune cells offer valuable insights into disease progression. This review presents a comprehensive analysis summarizing the relationship between CKs and SCZ and emphasizes the vital role of CKs encapsulated within EVs in the pathogenesis and development of SCZ.

Neuropsychiatric disorders denote a broad range of illnesses involving neurology and psychiatry. These disorders include depressive disorders, anxiety, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, autism spectrum disorders, headaches, and epilepsy. In addition to their main neuropathology that lies in the central nervous system (CNS), lately, studies have highlighted the role of immunity and neuroinflammation in neuropsychiatric disorders. Toll-like receptors (TLRs) are innate receptors that act as a bridge between the innate and adaptive immune systems via adaptor proteins (e.g., MYD88) and downstream elements; TLRs are classified into 13 families that are involved in normal function and illnesses of the CNS. TLRs expression affects the course of neuropsychiatric disorders, and is influenced during their pharmacotherapy; For example, the expression of multiple TLRs is normalized during the major depressive disorder pharmacotherapy. Here, the role of TLRs in neuroimmunology, treatment, and management of neuropsychiatric disorders is discussed. We recommend longitudinal studies to comparatively assess the cell-type-specific expression of TLRs during treatment, illness progression, and remission. Also, further research should explore molecular insights into TLRs regulation and related pathways.

Increasing evidence suggests that early life stress (ELS) and neuroinflammation are associated with the pathophysiology of depression. The purpose of this study was to determine the effects of Vortioxetine (VOR), a novel antidepressant, on ELS-induced behavioral changes and neuroinflammation.

Wistar Albino 4-week-old male rats were divided into four groups: control; chronic unpredictable stress (CUMS), VOR, CUMS + VOR. Neurobehavioral assessment was performed on the first, 21st, and 42nd days. RT-PCR was used to detect the expression of P2X7, NLRP3, IL1β, IL18 in the prefrontal cortex. To assess the microglial activities of the prefrontal cortex, immunohistochemically stained CD68, and leukocyte common antigen (LCA) preparations were scanned with Manual WSI software, Basler camera, and scored.

Exposure to CUMS was associated with depression and anxiety-like behaviors, and administration of VOR led to improvement in these behaviors. NLRP3, IL-1β, and IL-18 were shown to be upregulated in the prefrontal cortex of CUMS rats, while their high expression was inhibited by VOR treatment. CD68 and LCA expressions were significantly higher in the CUMS group compared to the other groups.

According to these results, it may be considered that NLRP3 inflammasome-associated neuroinflammatory response and microglial activation may play a role in the etiopathogenesis of ELS.

There is a complex interrelationship between the nervous system and the cardiovascular system. Comorbidities of cardiovascular diseases (CVD) with mental disorders, and vice versa, are prevalent. Adults with mental disorders such as anxiety and depression have a higher risk of developing CVD, and people with CVD have an increased risk of being diagnosed with mental disorders. Oxidative stress is one of the many pathways associated with the pathophysiology of brain and cardiovascular disease. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is one of the major generators of reactive oxygen species (ROS) in mammalian cells, as it is the enzyme that specifically produces superoxide. This review summarizes recent findings on the consequences of NOX activation in thrombosis and depression. It also discusses the therapeutic effects and pharmacological strategies of NOX inhibitors in CVD and brain disorders. A better comprehension of these processes could facilitate the development of new therapeutic approaches for the prevention and treatment of the comorbidity of thrombosis and depression.

Individuals with schizophrenia suffer from higher morbidity and mortality throughout life partly due to acceleration of aging-related diseases and conditions. Systemic inflammation is a hallmark of aging and is also observed in schizophrenia. An improved understanding of how inflammation and accelerated aging contribute to long-term health outcomes in schizophrenia could provide more effective treatments to preserve long-term cognitive and physical function. In this pilot cross-sectional study, 24 older adults (≥55 years old) with schizophrenia were assessed on symptoms (Positive and Negative Syndrome Scale), neurocognition (Matrics Consensus Cognitive Battery), mobility (Timed Get Up and Go), and general health (SF-12). Serum levels of 112 different cytokines were measured, from which we derived estimated senescence-associated secretory phenotype (SASP) scores for each participant. Two-tailed Pearson's bivariate correlations were computed to test the associations between schizophrenia clinical outcomes with individual cytokines, and SASP. Higher levels of eotaxin, IL-1α, IL-1β, and IFNα are associated with both worse PANSS negative and depressive symptoms scores. IL-1α and IL-1β negatively associated with general physical health whereas eotaxin negatively associated with mobility and global cognition. Overall, we found that specific inflammatory cytokines, but not composite measurements of SASP, are associated with clinical outcomes in older adults with schizophrenia.

Cyanobacterium Nostoc commune has long been used to alleviate various diseases. This research examines the effects of Nostoc commune extract (NCE) against behavioral disorders, cerebral oxidative stress, and inflammatory damage in the ketamine-induced schizophrenia model. Oral NCE administration (70 and 150 mg/kg/d) is performed after intraperitoneal ketamine injection (20 mg/kg) for 14 consecutive days. The forced swimming and open field tests are used to assess schizophrenia-like behaviors. After the behavioral test, dopamine (DA) level, oxidative stress markers, as well as the interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) expression are measured in the cerebral cortex. The results show that NCE treatment ameliorates KET-induced anxiety and depressive-like behaviors in OFT and FST, respectively. NCE considerably decreases the malondialdehyde (MDA) and DA levels and IL-6 and TNF-α expressions in mice with schizophrenia-like symptoms. Also, a significant increase is observed in the glutathione (GSH) level and catalase (CAT), superoxide dismutase (SOD), and glutathione reductase (GRx) activity in cerebral tissue. The present study shows that NCE treatment effectively improves KET-induced schizophrenia-like behaviors and oxidative and inflammatory damage. Therefore, NCE, via its bioactive constituents, could have strong neuroprotective effects in the schizophrenia-like model.

Glaucoma is the most common optic neuropathy and the leading cause of irreversible blindness worldwide, which affects 3.54% of the population aged 40-80 years. Despite numerous published studies, some aspects of glaucoma pathogenesis, serum biomarkers, and their potential link with other diseases remain unclear. Recent articles have proposed that autoimmune, oxidative stress and inflammation may be involved in the pathogenesis of glaucoma.

We investigated the serum expression of 92 inflammatory and neurotrophic factors in glaucoma patients. The study group consisted of 26 glaucoma patients and 192 healthy subjects based on digital fundography.

Patients with glaucoma had significantly lower serum expression of IL-2Rβ, TWEAK, CX3CL1, CD6, CD5, LAP TGF-beta1, LIF-R, TRAIL, NT-3, and CCL23 and significantly higher expression of IL-22Rα1.

Our results indicate that patients with glaucoma tend to have lower levels of neuroprotective proteins and higher levels of neuroinflammatory proteins, similar to those observed in psychiatric, neurodegenerative and autoimmune diseases, indicating a potential link between these conditions and glaucoma pathogenesis.

With its high prevalence, depression's pathogenesis remains unclear. Recent attention has turned to the interplay between depression and epigenetic modifications. However, quantitative bibliometric analyses are lacking. This study aims to visually analyze depression epigenetics trends, utilizing bibliometric tools, while comprehensively reviewing its epigenetic mechanisms.

Utilizing the Web of Science core dataset, we collected depression and epigenetics-related studies. Employing VOSViewer software, we visualized data on authors, countries, journals, and keywords. A ranking table highlighted field leaders.

Analysis encompassed 3,469 depression epigenetics studies published from January 2002 to June 2023. Key findings include: (1) Gradual publication growth, peaking in 2021; (2) The United States and its research institutions leading contributions; (3) Need for enhanced collaborations, spanning international and interdisciplinary efforts; (4) Keyword clustering revealed five main themes-early-life stress, microRNA, genetics, DNA methylation, and histone acetylation-highlighting research hotspots; (5) Limited focus on adolescent depression epigenetics, warranting increased attention.

Taken together, this study revealed trends and hotspots in depression epigenetics research, underscoring global collaboration, interdisciplinary fusion, and multi-omics data's importance. It discussed in detail the potential of epigenetic mechanisms in depression diagnosis and treatment, advocating increased focus on adolescent research in this field. Insights aid researchers in shaping their investigative paths toward understanding depression's epigenetic mechanisms and antidepressant interventions.

Post-stroke depression (PSD) affects approximately one-third of stroke survivors, severely impacting general recovery and quality of life. Despite extensive studies, the exact mechanisms underlying PSD remain elusive. However, emerging evidence implicates proinflammatory cytokines, including interleukin-1β, interleukin-6, tumor necrosis factor-alpha, and interleukin-18, play critical roles in PSD development. These cytokines contribute to PSD through various mechanisms, including hypothalamic-pituitary-adrenal (HPA) axis dysfunction, neurotransmitter alterations, neurotrophic factor changes, gut microbiota imbalances, and genetic predispositions. This review is aimed at exploring the role of cytokines in stroke and PSD while identifying their potential as specific therapeutic targets for managing PSD. A more profound understanding of the mechanisms regulating inflammatory cytokine expression and anti-inflammatory cytokines like interleukin-10 in PSD may facilitate the development of innovative interventions to improve outcomes for stroke survivors experiencing depression.

Interleukin 18 (IL18) was originally identified as an inflammation-induced cytokine that is secreted by immune cells. An increasing number of studies have focused on its non-immunological functions, with demonstrated functions for IL18 in energy homeostasis and neural stability. IL18 is reportedly required for lipid metabolism in the liver and brown adipose tissue. Furthermore, IL18 (Il18) deficiency in mice leads to mitochondrial dysfunction in hippocampal cells, resulting in depressive-like symptoms and cognitive impairment. Microarray analyses of Il18-/- mice have revealed a set of genes with differential expression in liver, brown adipose tissue, and brain; however, the impact of IL18 deficiency in these tissues remains uncertain. In this review article, we discuss these genes, with a focus on their relationships with the phenotypic disease traits of Il18-/- mice.

Major Depressive Disorder (MDD) is a common mental ailment and is the primary reason for disability. It manifests a severe impact on moods, thoughts, and physical health. At present, this disorder has become a concern in the field of public health. Alteration of neurochemicals is thought to be involved in the pathogenesis of many psychiatric disorders. Therefore, we aimed to evaluate serum IL-3 and lipocalin-2 in MDD patients and healthy controls (HCs).

We included a total of 376 participants in this study. Among them, 196 were MDD patients, and 180 were age-sex-matched HCs. MDD patients were recruited from the Psychiatry Department of Bangabandhu Sheikh Mujib Medical University (BSMMU), but the controls were from different parts of Dhaka. All study participants were evaluated by a psychiatrist using the DSM-5 criteria. To assess the severity of the depression, we used the Hamilton depression (Ham-D) rating scale. Serum IL-3 and lipocalin-2 levels were measured using commercially available enzyme-linked immune-sorbent assay kits (ELISA kits).

According to this study, we observed elevated serum levels of IL-3 (1,024.73 ± 29.84 pg/mL) and reduced levels of serum lipocalin-2 (29.019 ± 2.073 ng/mL) in MDD patients compared to HCs (911.11 ± 20.55 pg/mL and 48.065 ± 3.583 ng/mL, respectively). No associations between serum levels of IL-3 and lipocalin-2 and depression severity were observed in patients.

According to the present findings, alterations of serum IL-3 and lipocalin might be associated with the pathogenesis of MDD. These results support that altered serum neurochemicals can serve as early risk assessment markers for depression. Further interventional studies are recommended for a better understanding of the role of IL-3 and lipocalin-2 in the pathophysiology of depression.

Recent studies on the schizophrenia spectrum and other psychotic disorders showed that alternation of immune system components, particularly microRNAs (miRNAs) and pro-inflammatory compounds, plays a significant role in developing the illness. The study aimed to evaluate serum expression of the miRNA-26a, miRNA-106a, and miRNA-125b as genetic factors and serum levels of IL-6, IL-1β, and TNF-α as pro-inflammatory factors in an IranianAzeri population.

Forty patients with recent-onset non-affective psychosis and 40 healthy people as a control group were involved. Expression levels of miRNAs and serum levels of the cytokines were measured using RT-qPCR and ELISA, respectively. T-test, receiver operating characteristics (ROC), and spearman correlation coefficient were carried out data analysis.

Findings showed higher levels of IL-6, IL-1β, TNF-α, miR-26a, and miR-106a in the plasma of the patients' group compared with the control. miRNA-26a showed a statistically significant higher level (p < .003) compared to the control group, with AUC = 0.84 (95% CI: 0.77 to 0.93, P < .001) and cut-off point = 0.17 in comparison to other miRNAs as mentioned above; in this regard, it might be a suggestive biomarker for schizophrenia in the early stage of the illness. Moreover, miRNAs' expression level was not substantially associated with the level of any measured cytokines above.

miR-26a might be a suggestive biomarker for schizophrenia in the early stage of the illness. Given that the relationship between other miRNAs and cytokines is not yet well understood; accordingly, there are encouragement and support for continued research in this fascinating field.

People with HIV are at increased risk for depression, though the neurobiological mechanisms underlying this are unclear. In the last decade, there has been a substantial rise in interest in the contribution of (neuro)inflammation to depression, coupled with rapid advancements in the resolution and sensitivity of biomarker assays such as Luminex, single molecular array and newly developed positron emission tomography radioligands. Numerous pre-clinical and clinical studies have recently leveraged these next-generation immunoassays to identify biomarkers that may be associated with HIV and depression (separately), though few studies have explored these biomarkers in co-occurring HIV and depression. Using a systematic search, we detected 33 publications involving a cumulative N = 10 590 participants which tested for associations between depressive symptoms and 55 biomarkers of inflammation and related processes in participants living with HIV. Formal meta-analyses were not possible as statistical reporting in the field was highly variable; future studies must fully report test statistics and effect size estimates. The majority of included studies were carried out in the United States, with samples that were primarily older and primarily men. Substantial further work is necessary to diversify the geographical, age, and sex distribution of samples in the field. This review finds that alterations in concentrations of certain biomarkers of neuroinflammation (interleukin-6, tumour necrosis factor-α, neopterin) may influence the association between HIV and depression. Equally, the chemokines monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) or the metabolic index kynurenine:tryptophan (Kyn:Trp), which have been the focus of several studies, do not appear to be associated with depressive symptoms amongst people living with HIV, as all (MCP-1) or most (IL-8 and Kyn:Trp) available studies of these biomarkers reported non-significant associations. We propose a biomarker-driven hypothesis of the neuroimmunometabolic mechanisms that may precipitate the increased risk of depression among people with HIV. Chronically activated microglia, which trigger key neuroinflammatory cascades shown to be upregulated in people with HIV, may be the central link connecting HIV infection in the central nervous system with depressive symptoms. Findings from this review may inform research design in future studies of HIV-associated depression and enable concerted efforts towards biomarker discovery.

In addition to their traditional roles in immune cell communication, cytokines regulate brain development. Cytokines are known to influence neural cell generation, differentiation, maturation, and survival. However, most work on the role of cytokines in brain development investigates rodents or focuses on prenatal events. Here, we investigate how mRNA and protein levels of key cytokines and cytokine receptors change during postnatal development of the human prefrontal cortex. We find that most cytokine transcripts investigated (IL1B, IL18, IL6, TNF, IL13) are lowest at birth and increase between 1.5 and 5 years old. After 5 years old, transcriptional patterns proceeded in one of two directions: decreased expression in teens and young adults (IL1B, p = 0.002; and IL18, p = 0.004) or increased mean expression with maturation, particularly in teenagers (IL6, p = 0.004; TNF, p = 0.002; IL13, p < 0.001). In contrast, cytokine proteins tended to remain elevated after peaking significantly around 3 years of age (IL1B, p = 0.012; IL18, p = 0.026; IL6, p = 0.039; TNF, p < 0.001), with TNF protein being highest in teenagers. An mRNA-only analysis of cytokine receptor transcripts found that early developmental increases in cytokines were paralleled by increases in their ligand-binding receptor subunits, such as IL1R1 (p = 0.033) and IL6R (p < 0.001) transcripts. In contrast, cytokine receptor-associated signaling subunits, IL1RAP and IL6ST, did not change significantly between age groups. Of the two TNF receptors, the 'pro-death' TNFRSF1A and 'pro-survival' TNFRSF1B, only TNFRSF1B was significantly changed (p = 0.028), increasing first in toddlers and again in young adults. Finally, the cytokine inhibitor, IL13, was elevated first in toddlers (p = 0.006) and again in young adults (p = 0.053). While the mean expression of interleukin-1 receptor antagonist (IL1RN) was highest in toddlers, this increase was not statistically significant. The fluctuations in cytokine expression reported here support a role for increases in specific cytokines at two different stages of human cortical development. The first is during the toddler/preschool period (IL1B, IL18, and IL13), and the other occurs at adolescence/young adult maturation (IL6, TNF and IL13).

Schizophrenia (SCZ) is a severe, protracted neurological disorder that causes disruptive conduct in millions of individuals globally. Discovery of potential biomarkers in clinical settings would lead to the development of efficient diagnostic techniques and an awareness of the disease's pathogenesis and prognosis. The aim of the present study was to discover and identify serum complement factor-based biomarkers in discriminating patients with first-episode SCZ from healthy controls.

Eighty-nine patients with first-episode SCZ and 89 healthy controls were included in this study. Psychiatric symptom severity of patients with SCZ was measured with the Brief Psychiatric Rating Scale-18 Item Version (BPRS) and the Scales for the Assessment of Negative/Positive Symptoms (SANS/SAPS). A total of 5 complement factors including complement component 1 (C1), C2, C3, C4, and 50% hemolytic complement (CH50) were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits. The levels of serum complement factors in the SCZ and control groups were compared, and the receiver operating characteristic (ROC) curve method was used to assess the diagnostic values of various complement factors for separating SCZ patients from healthy controls. Pearson's correlation test was used to assess the relationships between serum complement factor concentrations and the psychiatric symptom severity.

There was an increase in serum levels of C1, C2, C3, C4, and CH50 among patients with SCZ. Moreover, based on ROC curve analysis, the AUC value of a combined panel of C1, C2, C3, C4, and CH50 was 0.857 when used to discriminate patients with SCZ from healthy controls. Furthermore, serum C2, C3, and CH50 levels were positively correlated to the scores of SANS, SAPS, and BPRS in patients with SCZ, respectively.

These results suggested that circulating complement factors including C1, C2, C3, C4, and CH50 may have potential in discovering biomarkers for diagnosing first-episode SCZ.

Upregulation of genes and coexpression networks related to immune function and inflammation have been repeatedly reported in the brain of individuals with schizophrenia. However, a causal relationship between the abnormal immune/inflammation-related gene expression and schizophrenia has not been determined. We conducted co-expression networks using publicly available RNA-seq data from prefrontal cortex (PFC) and hippocampus (HP) of 64 individuals with schizophrenia and 64 unaffected controls from the SMRI tissue collections. We identified proinflammatory cytokine, transmembrane tumor necrosis factor-α (tmTNFα), as a potential regulator in the module of co-expressed genes that we find related to the immune/inflammation response in endothelial cells (ECs) and/or microglia of the brain of individuals with schizophrenia. The immune/inflammation-related modules associated with schizophrenia and the TNF signaling pathway that regulate the network were replicated in an independent cohort of brain samples from 68 individuals with schizophrenia and 135 unaffected controls. To investigate the association between the overexpression of tmTNFα in brain ECs and schizophrenia-like behaviors, we induced short-term overexpression of the uncleavable form of (uc)-tmTNFα in ECs of mouse brain for 7 weeks. We found schizophrenia-relevant behavioral deficits in these mice, including cognitive impairment, abnormal sensorimotor gating, and sensitization to methamphetamine (METH) induced locomotor activity and METH-induced neurotransmitter levels. These uc-tmTNFα effects were mediated by TNF receptor2 (TNFR2) and induced activation of TNFR2 signaling in astrocytes and neurons. A neuronal module including neurotransmitter signaling pathways was down-regulated in the brain of mice by the short-term overexpression of the gene, while an immune/inflammation-related module was up-regulated in the brain of mice after long-term expression of 22 weeks. Our results indicate that tmTNFα may play a direct role in regulating neurotransmitter signaling pathways that contribute to the clinical features of schizophrenia.

Depression is one of the leading mental illnesses worldwide and lowers the quality of life of many. According to WHO, about 5% of the worldwide population suffers from depression. Newer studies report a staggering global prevalence of 27.6%, and it is rising. Professionally, depression belonging to affective disorders is a psychiatric illness, and the category of major depressive disorder (MDD) comprises various diagnoses related to persistent and disruptive mood disorders. Due to this fact, it is imperative to find a way to assess depression quantitatively using a specific biomarker or a panel of biomarkers that would be able to reflect the patients' state and the effects of therapy. Cytokines, hormones, oxidative stress markers, and neuropeptides are studied in association with depression. The latest research into inflammatory cytokines shows that their relationship with the etiology of depression is causative. There are stronger cytokine reactions to pathogens and stressors in depression. If combined with other predisposing factors, responses lead to prolonged inflammatory processes, prolonged dysregulation of various axes, stress, pain, mood changes, anxiety, and depression. This review focuses on the most recent data on cytokines as markers of depression concerning their roles in its pathogenesis, their possible use in diagnosis and management, their different levels in bodily fluids, and their similarities in animal studies. However, cytokines are not isolated from the pathophysiologic mechanisms of depression or other psychiatric disorders. Their effects are only a part of the whole pathway.

There is increasing evidence that oxidative stress (OS) and neuroinflammation play a role in the neuroprogression of schizophrenia (SCZ). Promising novel candidates which have been proposed in the search for biomarkers of psychotic illness include NADPH oxidase 1,2 (NOX1,2) and raftlin. NOX1 from the NOX family is the main source of physiological reactive oxygen species (ROS) and raftlin, the main lipid raft protein, is associated with inflammatory processes. The aim of the present study was to evaluate serum NOX1 and raftlin levels in chronic stable patients with SCZ.

We measured serum NOX1 and raftlin levels from 45 clinically stable patients with SCZ and 45 healthy controls (HCs) matched for age, sex, and body-mass index. The Positive and Negative Syndrome Scale was applied to the patient group to evaluate the severity of psychotic symptoms.

NOX1 and raftlin levels in the patients were statistically significantly higher than the HCs (NOX1 p<0.001, raftlin p<0.001). Both parameters showed very good diagnostic performance (NOX1 AUC = 0.931, raftlin AUC = 0.915). We obtained positive and significant correlations between serum levels of both biomarkers and symptom severity.

This preliminary study indicating elevations in serum NOX1 and raftlin levels in patients with SCZ supports the importance of OS and inflammatory processes in the etiopathogenesis of the illness.

In people with schizophrenia, major areas of everyday life are impaired, including independent living, productive activities, social relationships and overall quality of life. Enhanced understanding of factors that hinder real-life functioning is vital for treatments to translate into more positive outcomes.

The goal of the present study was to identify factors associated with motivation deficits in real-life schizophrenia, and to assess its contribution to impaired functioning and quality of life.

Based on previous literature and clinical experience, several factors were selected and grouped into factors potentially explaining motivation deficits. Some of these variables were never investigated before in relationship with motivation deficits.

In 561 patients with schizophrenia of the national FACE-SZ cohort living in the community, 235 (41.9%) reported severe motivation deficits. These deficits were found to be significantly associated with impaired socially useful activities, psychological and physical quality of life (in almost all domains), alcohol use disorder (aOR = 2.141, p = 0.021), severe nicotine dependence (aOR = 2.906, p < 0.001) independently of age and sex. No significant association was found for body mass index, metabolic syndrome or physical activity level. In the second model, we identified the following modifiable factors associated with motivation deficits: history of suicide attempt (aOR = 2.297, p = 0.001), positive symptoms (aOR = 1.052, p = 0.006), current major depressive episode (aOR = 2.627, p < 0.001), sleep disorders (aOR = 1.474, p = 0.024) and lower medication adherence (aOR = 0.836, p = 0.001) independently of gender, current alcohol use disorder, second-generation antipsychotics and akathisia. No significant association was found for negative symptoms, childhood trauma and inflammation. These results were maintained after removing patients with schizoaffective disorders or those with major depressive disorder.

Motivation deficits are frequent and remain persistent unmet need in real-world schizophrenia that should be addressed in future guidelines. Based on our results, literature and clinical experience, we recommend to address in priority major depression, sleep, suicide, positive symptoms (when present and as early as possible) and medication adherence to improve motivation deficits of schizophrenia.

Interleukin-18 (IL18) is an inflammatory cytokine that is related to psychiatric disorders such as depression and cognitive impairment. We previously found that IL18 deficiency may cause hippocampal impairment, resulting in depression-like behavioral changes. However, the potential role of IL18 in stressful conditions remains uncertain. In the present study, we examined the effect of IL18 on neural inflammation and stress tolerance during acute stress. Littermate Il18^+/+ and Il18^-/- mice were exposed to a single restraint stress for 6 h, and all assessments were performed 18 h after the mice were released from the restraint. In Il18^-/- mice exposed to acute stress, the immobility times in both the forced swim test and tail suspension test were decreased, although no difference was observed in Il18^+/+ mice. Il1β, Il6, and Tnfα expression levels in the hippocampus of stressed Il18^-/- mice were significantly higher than those in the other groups. Moreover, the numbers of astrocytes and microglia, including those in the active form, were also increased compared with those in other groups. Regarding the molecular mechanism, the HSF5 and TTR genes were specifically expressed in stressed Il18^-/- mice. As a potential treatment, intracerebral administration of IL18 to Il18^-/- mice resulted in partial recovery of changes in behavioral assessments. Our results revealed that IL18-deficient mice were more sensitive and had a longer response to acute stress than that in normal mice. In addition, neural inflammation and augmentation of glucocorticoid signals caused by stress were more intense and remained longer in Il18^-/- mice, resulting in behavioral changes. In conclusion, IL18 might be an indispensable factor that modulates the stress response and maintains balance between neural inflammation and glucocorticoid signaling.

Interleukin-18 (IL-18) may participate in the development of major depressive disorder, but the specific mechanism remains unclear. This study aimed to explore whether IL-18 correlates with areas of the brain associated with depression.

Using a case-control design, 68 subjects (34 patients and 34 healthy controls) underwent clinical assessment, blood sampling, and resting-state functional Magnetic Resonance Imaging (fMRI). The total Hamilton depression-17 (HAMD-17) score was used to assess depression severity. Enzyme-linked immunosorbent assay (ELISA) was used to detect IL-18 levels. Rest-state fMRI was conducted to explore spontaneous brain activity.

The level of IL-18 was higher in patients with depression in comparison with healthy controls. IL-18 was negatively correlated with degree centrality of the left posterior cingulate gyrus in the depression patient group, but no correlation was found in the healthy control group.

This study suggests the involvement of IL-18 in the pathophysiological mechanism for depression and interference with brain activity.

Major depressive disorder (MDD) is a common condition that affects the general population over a wide range of ages, regardless of gender and social background. Early-onset of MDD in adulthood, between ages of 18 and 30 years, is associated with worse outcomes and increased years of disability. Stress load and physical health have been associated with age of onset in MDD. We aim to investigate whether early onset MDD might be associated with changes in systemic inflammatory markers. We examined levels of following cytokines: IL-1β, IL-6, IL-10 and TNFα in 234 patients with MDD. Higher serum levels of TNFα and IL-1β are associated with the early onset of the disorder in patients with MDD. IL-6 levels were also higher in the early onset group and IL-10 levels were higher in the late onset group, but with no significant difference. Changes in the anti-inflammatory/pro-inflammatory balance have been described in mood disorders and may be implicated in its severity and pattern of progression. Our findings reinforce that higher serum levels of IL-1β and TNFα may be associated with the earlier onset subgroup of MDD patients. Future research that target inflammatory markers of immune modulation may be, key in the search for novel preventative therapeutics.

Defensin Alpha 4 (DEFA4) is the fourth member of the Alpha Defensins family known as a part of antimicrobial peptides in the innate immune system. DEFA4 has a strong preference to kill Gram-negative bacteria more than Gram-positive bacteria. In addition, DEFA4 exhibits antiviral activity against human immunodeficiency virus type 1 (HIV-1) in vitro. Moreover, DEFA4 can act as an inhibitor of corticosterone production (Corticostatin). On the other hand, alternations in DEFA4 gene expression have been reported in different disorders such as diseases related to inflammation and immunity dysfunction, brain-related disorders, and various cancers. The up-regulation of DEFA4 appears to be involved in the malignant transformation or aggressive form of cancer. Interestingly, the modified version of DEFA4 fragment (1-11) was potent and efficient against antibiotic-resistant bacteria. This review provides a general background abSaudi Arabia out DEFA4 and sheds light on changes in DEFA4 gene expression in different diseases. The paper also discusses other aspects related to DEFA4 as an antimicrobial and antiviral agent. The research was conducted based on available articles obtained from databases starting from 1988 to the present.

It has been reported that childhood trauma and inflammation are associated with major depressive disorder (MDD) and schizophrenia (SZ), but previous researches were almost aimed at adults. The aim of the present research is to observe the alteration of peripheral interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in adolescents (12-20 years) with MDD and SZ, to investigate the impact of childhood abuse in early-onset MDD and SZ, and to furtherly explore the correlation between childhood maltreatment and plasma IL-6, TNF-α levels.

Enzyme-linked immunosorbent assay (ELISA) is applied to obtain the plasma concentrations of IL-6 and TNF-α in 55 patients with MDD, 51 patients with SZ and 47 healthy minors. The short form of the Childhood Trauma Questionnaire (CTQ-SF) is used to assess the severity of early trauma.

Plasma IL-6 and TNF-α levels are significantly elevated in patients with early-onset MDD and SZ compared with healthy subjects (p <0.01), whose results display that the correlation between IL-6 and TNF-α is significantly positive (γ=0.787, p <0.01) in all participants. Compared with the healthy adolescents, patients with MDD and SZ show more serious childhood trauma, and the plasma IL-6, TNF-α concentrations are closely related to childhood maltreatment.

Early trauma and peripheral inflammatory response play an important role in the pathophysiology of early-onset MDD or SZ. The current findings provide effective targets for the prevention, diagnosis, and treatment of major depressive disorder and schizophrenia in adolescents.

Elevations in plasma levels of pro-inflammatory cytokines and C-reactive protein (CRP) in patient blood have been associated with impairments in cognitive abilities and more severe psychiatric symptoms in people with schizophrenia. The transcription factor nuclear factor kappa B (NF-κB) regulates the gene expression of pro-inflammatory factors whose protein products trigger CRP release. NF-κB activation pathway mRNAs are increased in the brain in schizophrenia and are strongly related to neuroinflammation. Thus, it is likely that this central immune regulator is also dysregulated in the blood and associated with cytokine and CRP levels. We measured levels of six pro-inflammatory cytokine mRNAs and 18 mRNAs encoding NF-κB pathway members in peripheral blood leukocytes from 87 people with schizophrenia and 83 healthy control subjects. We then assessed the relationships between the alterations in NF-κB pathway genes, pro-inflammatory cytokine and CRP levels, psychiatric symptoms and cognition in people with schizophrenia. IL-1β and IFN-γ mRNAs were increased in patients compared to controls (both p < 0.001), while IL-6, IL-8, IL-18, and TNF-α mRNAs did not differ. Recursive two-step cluster analysis revealed that high levels of IL-1β mRNA and high levels of plasma CRP defined 'high inflammation' individuals in our cohort, and a higher proportion of people with schizophrenia were identified as displaying 'high inflammation' compared to controls using this method (p = 0.03). Overall, leukocyte expression of the NF-κB-activating receptors, TLR4 and TNFR2, and the NF-κB subunit, RelB, was increased in people with schizophrenia compared to healthy control subjects (all p < 0.01), while NF-κB-inducing kinase mRNAs IKKβ and NIK were downregulated in patients (all p < 0.05). We found that elevations in TLR4 and RelB appear more related to inflammatory status than to a diagnosis of schizophrenia, but changes in TNFR2 occur in both the high and low inflammation patients (but were exaggerated in high inflammation patients). Further, decreased leukocyte expression of IKKβ and NIK mRNAs was unique to high inflammation patients, which may represent schizophrenia-specific dysregulation of NF-κB that gives rise to peripheral inflammation in a subset of patients.

Our previous studies documented that interleukin-15 receptor α (IL-15Rα) knockout (KO) mice exhibited hyperactivity, memory impairment, and desperate behavior, which are core features of schizophrenia and depression. Due to the overlapping symptomology and pathogenesis observed for schizophrenia and depression, the present study attempted to determine whether IL-15Rα was associated with the risk of schizophrenia or depression. One hundred fifty-six participants, including 63 schizophrenia patients, 29 depressive patients, and 64 age-matched healthy controls, were enrolled in the study. We investigated the circulating levels of soluble IL-15Rα and analyzed potential links between the IL-15Rα levels and clinical symptoms present in schizophrenia or depressive patients. We observed reduced serum IL-15Rα levels in schizophrenia patients, but not depressive patients compared with controls. Moreover, a significant negative association was observed between the circulating IL-15Rα levels and excited phenotypes in the schizophrenia patients. The IL-15Rα KO mice displayed pronounced pre-pulse inhibition impairment, which was a typical symptom of schizophrenia. Interestingly, the IL-15Rα KO mice exhibited a remarkable elevation in the startle amplitude in the startle reflex test compared to wild type mice. These results demonstrated that serum levels of soluble IL-15Rα were reduced in schizophrenia and highlighted the relationship of IL-15Rα and the excited phenotype in schizophrenia patients and mice.

A previous transcriptome meta-analysis revealed significantly lower levels of corticotropin-releasing hormone (CRH) mRNA in corticolimbic brain regions in major depressive disorder (MDD) subjects, suggesting that cortical CRH-expressing (CRH+) cells are affected in MDD. Rodent studies show that cortical CRH is mostly expressed in GABAergic interneurons; however, the characteristic features of CRH+ cells in human brain cortex and their association with MDD are largely unknown.

Subgenual anterior cingulate cortex (sgACC) of human subjects without brain disorders were labeled using fluorescent in situ hybridization (FISH) for CRH and markers of excitatory (SLC17A7), inhibitory (GAD1) neurons, as well as markers of other interneuron subpopulations (PVALB, SST, VIP). MDD-associated changes in CRH+ cell density and cellular CRH expression (n = 6/group) were analyzed. RNA-sequencing was performed on sgACC CRH+ interneurons from comparison and MDD subjects (n = 6/group), and analyzed for group differences. The effect of reduced BDNF on CRH expression was tested in mice with blocked TrkB function.

About 80% of CRH+ cells were GABAergic and 17.5% were glutamatergic. CRH+ GABAergic interneurons co-expressed VIP (52%), SST (7%), or PVALB (7%). MDD subjects displayed lower CRH mRNA levels in GABAergic interneurons relative to comparison subjects without changes in cell density. CRH+ interneurons show transcriptomic profile suggesting lower excitability and less GABA release and reuptake. Further analyses suggested that these molecular changes are not mediated by altered glucocorticoid feedback and potentially occur downstream for a common modulator of neurotrophic function.

CRH+ cells in human sgACC are a heterogeneous population of GABAergic interneurons, although largely co-expressing VIP. Our data suggest that MDD is associated with reduced markers of inhibitory function in sgACC CRH+ interneurons, and provide further evidence for impaired GABAergic function in the cortex in MDD.

Although schizophrenia is a severe mental illness, whose etiology is still largely unknown, its pathogenesis may be associated with dysregulation of the immune mechanisms. The present study compares the levels of interleukin (IL)-10, interleukin-8 (CXCL8), and fractalkine (CX3CL1) between schizophrenia patients and healthy controls. It also assesses the ability of peripheral peripheral blood mononuclear cells (PBMCs) to produce these cytokines spontaneously and following mitogen-stimulation.

A prospective study was performed of 60 adult schizophrenia patients and 32 controls. CXCL8, IL-10, and fractalkine concentrations were measured in serum and supernatants from cultured PBMCs. Anthropometric (BMI, WHR) and body composition measurements were taken using bioimpedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA).

The schizophrenia patients demonstrated significantly higher levels of serum CXCL8 (schizophrenia: 13.4 ± 15.7 pg/mL, control: 6.9 ± 4.2 pg/mL, p = 0.001) and lower level of serum fractalkine (schizophrenia: 22.8 ± 9.9 pg/mL, control: 45.4 ± 84.5 pg/mL, p = 0.041). Serum IL-10 levels did not significantly differ. No in vitro synthesis of fractalkine was observed. Neither unstimulated or PHA-stimulated CXCL8 secretion differed between the two groups (p >0.05). The patients not taking mood stabilizers (MS-) demonstrated significantly higher CXCL8 levels than those on mood stabilizers (MS+) (p = 0.03) and control (p < 0.001). In addition, the MS- sub-group demonstrated significantly lower serum fraktalkine than controls (p = 0.009). These effects could be described as pseudo-normalization of CXCL8 and fractalkine in schizophrenia patients taking mood stabilizers.