Inflammation: a mechanism of depression?
Ontology highlight
ABSTRACT:
SUBMITTER: Han QQ
PROVIDER: S-EPMC5562613 | biostudies-other | 2014 Jun
REPOSITORIES: biostudies-other
Similar Datasets
Project description:This paper describes the effects of immune genes genetic variants and mRNA expression on depression's risk, severity, and response to antidepressant treatment, through a systematic review on all papers published between 2000 and 2016. Our results, based largely on case-control studies, suggest that common genetic variants and gene-expression pathways are involved in both immune activation and depression. The most replicated and relevant genetic variants include polymorphisms in the genes for interleukin (IL)-1β, IL-6, IL-10, monocyte chemoattractant protein-1, tumor necrosis factor-alpha, C-reactive protein, and phospholipase A2. Moreover, increased blood cytokines mRNA expression (especially of IL-1β) identifies patients that are less likely to respond to conventional antidepressants. However, even for the most replicated findings there are inconsistent results, not only between studies, but also between the immune effects of the genetic variants and the resulting effects on depression. We find evidence that these discrepant findings may be explained, at least in part, by the heterogeneity of the depression immunophenotype, by environmental influences and gene × environment interactions, and by the complex interfacing of genetic variants with gene expression. Indeed, some of the most robust findings have been obtained in patients developing depression in the context of treatment with interferon-alpha, a widely used model to mimic depression in the context of inflammation. Further 'omics' approaches, through GWAS and transcriptomics, will finally shed light on the interaction between immune genes, their expression, and the influence of the environment, in the pathogenesis of depression.
| S-EPMC5143493 | biostudies-literature
Project description:Whole-genome, time-course data was developed from the lungs of influenza infected mice to better characterize the dynamics of the host immune response during infection. Lung for microarray studies were obtained from female, five-week old C57BL/6Js infected with influenza viruses. Forty-two animals per group were inoculated with 10^5 PFU of A/Kawasaki/UTK-4/09 H1N1 virus [Kawasaki], A/California/04/09 (H1N1) virus (pH1N1) [SOIV], A/Vietnam/1203/04 H5N1 virus (H5N1), 10^3 PFU A/Vietnam/1203/04 H5N1 virus (H5N1) [VN1203] or mock-infected with PBS. Spanning the first week of the infections, three animals per infection group were sacrificed at 14 predetermined time points, lungs isolated and the homogenate was used to assess changes in genes expression over time and between infections.
2015-06-12 | E-GEOD-63786 | biostudies-arrayexpress
Project description:Spreading depression (SD) is an intense and prolonged depolarization in the central nervous systems from insect to man. It is implicated in neurological disorders such as migraine and brain injury. Here, using an in vivo mouse model of focal neocortical seizures, we show that SD may be a fundamental defense against seizures. Seizures induced by topical 4-aminopyridine, penicillin or bicuculline, or systemic kainic acid, culminated in SDs at a variable rate. Greater seizure power and area of recruitment predicted SD. Once triggered, SD immediately suppressed the seizure. Optogenetic or KCl-induced SDs had similar antiseizure effect sustained for more than 30 min. Conversely, pharmacologically inhibiting SD occurrence during a focal seizure facilitated seizure generalization. Altogether, our data indicate that seizures trigger SD, which then terminates the seizure and prevents its generalization.
| S-EPMC8044138 | biostudies-literature
Project description:The Toll-interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP) represents a key intracellular signalling molecule regulating diverse immune responses. Its capacity to function as an adaptor molecule has been widely investigated in relation to Toll-like Receptor (TLR)-mediated innate immune signalling. Since the discovery of TIRAP in 2001, initial studies were mainly focused on its role as an adaptor protein that couples Myeloid differentiation factor 88 (MyD88) with TLRs, to activate MyD88-dependent TLRs signalling. Subsequent studies delineated TIRAP's role as a transducer of signalling events through its interaction with non-TLR signalling mediators. Indeed, the ability of TIRAP to interact with an array of intracellular signalling mediators suggests its central role in various immune responses. Therefore, continued studies that elucidate the molecular basis of various TIRAP-protein interactions and how they affect the signalling magnitude, should provide key information on the inflammatory disease mechanisms. This review summarizes the TIRAP recruitment to activated receptors and discusses the mechanism of interactions in relation to the signalling that precede acute and chronic inflammatory diseases. Furthermore, we highlighted the significance of TIRAP-TIR domain containing binding sites for several intracellular inflammatory signalling molecules. Collectively, we discuss the importance of the TIR domain in TIRAP as a key interface involved in protein interactions which could hence serve as a therapeutic target to dampen the extent of acute and chronic inflammatory conditions.
| S-EPMC8297548 | biostudies-literature
Project description:The biological underpinnings of major depressive disorder (MDD) heterogeneity are unknown, in part due to the poor association between MDD models and clinical endpoints. We compared transcriptomic profiles of human postmortem MDD brain tissue and chronic variable stress (CVS)-exposed mice to identify orthologous genes. A downregulation of ribosomal protein genes (RPGs) and upregulation of associated RP pseudogenes in the prefrontal cortex of several independent cohorts from both human MDD and mouse CVS tissue prompted a seeded gene co-expression analysis using the RPGs altered in both groups. Downregulated RPGs were found to regulate synaptic changes in human MDD and mouse CVS through a RP pseudogene-driven mechanism. In vitro and in silico analysis further suggested that the inverse RPG/RP pseudogene association was a glucocorticoid-driven response and reversed during MDD remission. Thus, stress-induced alterations in RPGs may contribute to synaptic dysregulation in MDD, providing a mechanism for the variability in depression presentation.
2023-10-25 | GSE229905 | GEO
Project description:Depression is a common and disabling disorder, representing a major social and economic health issue. Moreover, depression is associated with the progression of diseases with an inflammatory etiology including many inflammatory-related disorders. At the molecular level, the mechanisms by which depression might promote the onset of these diseases and associated immune-dysfunction are not well understood. In this study we assessed genome-wide patterns of DNA methylation in whole blood-derived DNA obtained from individuals with a self-reported history of depression (n=100) and individuals without a history of depression (n=100) using the Illumina 450K microarray. Our analysis identified 6 significant (Sidak corrected P < 0.05) depression-associated differentially methylated regions (DMRs); the top-ranked DMR was located in exon 1 of the LTB4R2 gene (Sidak corrected P = 1.27 x 10-14). Polygenic risk scores (PRS) for depression were generated and known biological markers of inflammation, telomere length (TL) and IL-6, were measured in DNA and serum samples respectively. Next, we employed a systems-level approach to identify networks of co-methylated loci associated with a history of depression, in addition to depression PRS, TL and IL-6 levels. Our analysis identified one depression-associated co-methylation module (P = 0.04). Interestingly, the depression-associated module was highly enriched for pathways related to immune function and was also associated with TL and IL-6 cytokine levels. In summary, our genome-wide DNA methylation analysis of individuals with and without a self-reported history of depression identified several candidate DMRs of potential relevance to the pathogenesis of depression and its associated immune-dysfunction phenotype.
2018-06-01 | GSE113725 | GEO
Project description:BackgroundDepression rates increase markedly for girls across the adolescent transition, but the social-environmental and biological processes underlying this phenomenon remain unclear. To address this issue, we tested a key hypothesis from Social Signal Transduction Theory of Depression, which posits that individuals who mount stronger inflammatory responses to social stress should exhibit greater increases in depressive symptoms following interpersonal life stress exposure than those who mount weaker inflammatory responses to such stress.MethodParticipants were 116 adolescent girls (Mage = 14.71) at risk for psychopathology, defined as having a history of mental health concerns (e.g., psychiatric treatment, significant symptoms) over the past 2 years. At baseline, we characterized their inflammatory reactivity to social stress by quantifying their salivary proinflammatory cytokine responses to a laboratory-based social stressor. Then, 9 months later, we assessed the interpersonal and noninterpersonal stressful life events that they experienced over the prior 9 months using an interview-based measure of life stress.ResultsAs hypothesized, greater interpersonal life stress exposure was associated with significant increases in depression over time, but only for girls exhibiting stronger salivary tumor necrosis factor-α and interleukin-1β reactivity to social stress. In contrast, noninterpersonal stress exposure was unrelated to changes in depression longitudinally, both alone and when combined with youths' cytokine reactivity scores.DiscussionThese results are consistent with Social Signal Transduction Theory of Depression and suggest that heightened inflammatory reactivity to social stress may increase adolescents' risk for depression. Consequently, it may be possible to reduce depression risk by modifying inflammatory responses to social stress.
| S-EPMC7000138 | biostudies-literature
Project description:Increased inflammation and oxidative stress have been shown in Major Depressive Disorder (MDD), although there is significant heterogeneity across studies. Whether markers of inflammation and oxidative stress are associated with antidepressant treatment response in MDD is currently unclear. The goals of the present study are to investigate markers of inflammation and oxidative stress in unmedicated MDD subjects and controls and test the relationship between these markers and antidepressant response in MDD subjects.Interleukin (IL)-6, tumor necrosis factor (TNF)-?, C-reactive protein, F2-isoprostanes, 8-OH 2-deoxyguanosine (8-OHdG), glutathione peroxidase, glutathione, and vitamin C were quantified in blood samples from 50 unmedicated MDD subjects and 55 healthy controls. Depression symptom severity was rated with the 17-item Hamilton Depression Rating Scale (HDRS). All subjects were somatically healthy and free from medications that could interfere with inflammation and oxidative stress markers. A subgroup of 22 MDD subjects underwent open-label selective serotonin reuptake inhibitor (SSRI) antidepressant treatment for eight weeks, after which blood sampling and the HDRS were repeated. Antidepressant treatment "response" was defined as ?50% decrease in HDRS ratings over 8 weeks of treatment.After controlling for the effects of age, sex, body mass index and smoking, MDD subjects had significantly higher levels of IL-6 (p<0.001), TNF-? (p<0.001), 8-OHdG (p=0.018), and F2-isoprostanes (p=0.012). Compared to Responders, Non-responders to SSRI antidepressant treatment had higher levels of F2-isoprostanes at baseline (p=0.006), and after eight weeks of treatment (p=0.031). Non-responders showed a significant increase in 8-OHdG over the course of treatment (p=0.021), whereas Responders showed a significant decrease in IL-6 over the course of treatment (p=0.019).Our results are in line with previous reports of increased levels of markers of inflammation and oxidative stress in MDD. Moreover, poorer antidepressant treatment response was related to higher baseline levels of the major oxidative stress marker, F2-isoprostanes, in vivo. Further, antidepressant response was associated with changes in oxidative (8-OHdG) and inflammatory (IL-6) markers.
| S-EPMC5272818 | biostudies-literature
Project description:Major depression during pregnancy is a common psychiatric disorder that arises from a complex and multifactorial etiology. Psychosocial stress, sex, hormones, and genetic vulnerability increase the risk for triggering mood disorders. Microglia and toll-like receptor 4 play a crucial role in triggering wide and varied stress-induced responses mediated through activation of the inflammasome; this leads to the secretion of inflammatory cytokines, increased serotonin metabolism, and reduction of neurotransmitter availability along with hypothalamic-pituitary-adrenal axis hyperactivity. Dysregulation of this intricate neuroimmune communication network during pregnancy modifies the maternal milieu, enhancing the emergence of depressive symptoms and negative obstetric and neuropsychiatric outcomes. Although several studies have clearly demonstrated the role of the innate immune system in major depression, it is still unclear how the placenta, the brain, and the monoaminergic and neuroendocrine systems interact during perinatal depression. Thus, in the present review we describe the cellular and molecular interactions between these systems in major depression during pregnancy, proposing that the same stress-related mechanisms involved in the activation of the NLRP3 inflammasome in microglia and peripheral myeloid cells in depressed patients operate in a similar fashion in the neuroimmune placenta during perinatal depression. Thus, activation of Toll-like receptor 2 and 4 signaling and the NLRP3 inflammasome in placental immune cells may promote a shift of the Th1/Th2 bias towards a predominant Th1/Th17 inflammatory response, associated with increased secretion of pro-inflammatory cytokines, among other secreted autocrine and paracrine mediators, which play a crucial role in triggering and/or exacerbating depressive symptoms during pregnancy.
| S-EPMC5563787 | biostudies-other
Project description:BackgroundMajor depressive disorder (MDD) represents a major public health concern, particularly due to its steadily rising prevalence and the poor responsiveness to standard antidepressants notably in patients afflicted with chronic inflammatory conditions, such as obesity. This highlights the need to improve current therapeutic strategies, including by targeting inflammation based on its role in the pathophysiology and treatment responsiveness of MDD. Nevertheless, dissecting the relative contribution of inflammation in the development and treatment of MDD remains a major issue, further complicated by the lack of preclinical depression models suitable to experimentally dissociate inflammation-related vs. inflammation-unrelated depression.MethodsWhile current models usually focus on one particular MDD risk factor, we compared in male C57BL/6J mice the behavioral, inflammatory and neurobiological impact of chronic exposure to high-fat diet (HFD), a procedure known to induce inflammation-related depressive-like behaviors, and unpredictable chronic mild stress (UCMS), a stress-induced depression model notably renowned for its responsivity to antidepressants.ResultsWhile both paradigms induced neurovegetative, depressive-like and anxiety-like behaviors, inflammation and downstream neurobiological pathways contributing to inflammation-driven depression were specifically activated in HFD mice, as revealed by increased circulating levels of inflammatory factors, as well as brain expression of microglial activation markers and enzymes from the kynurenine and tetrahydrobiopterin (BH4) pathways. In addition, serotoninergic and dopaminergic systems were differentially impacted, depending on the experimental condition.ConclusionsThese data validate an experimental design suitable to deeply study the mechanisms underlying inflammation-driven depression comparatively to non-inflammatory depression. This design could help to better understand the pathophysiology of treatment resistant depression.
| S-EPMC8666053 | biostudies-literature