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Toll-like receptor 4-mediated cytokine synthesis and post-stroke depressive symptoms.

ABSTRACT: Altered cytokine synthesis thought to contribute to the pathophysiology of post-stroke depression (PSD). Toll-like receptor 4 (TLR4) is a master regulator of innate immunity. The aim of this study was to explore the putative association between TLR4-mediated cytokine synthesis and subsequent symptoms of PSD. In total, 262 patients with ischemic stroke and without a history of PSD were included. Depressive symptoms were assessed using the Patient Health Questionnaire-9 in 170 patients on Day 8 and in 146 at 3 months after stroke. Blood samples taken on Day 3 after stroke were stimulated ex vivo with lipopolysaccharide (LPS). Ex vivo synthesized cytokines (TNFα, IP-10, IL-1β, IL-6, IL-8, IL-10, and IL-12p70) and circulating cytokines (TNFα, IL-6, sIL-6R, and IL-1ra) were measured using the enzyme-linked immunoassay or cytometric method. RNA sequencing was used to determine the gene expression profile of LPS-induced cytokines and chemokines. LPS-induced cytokine synthesis and the gene expression of TLR4-dependent cytokines and chemokines did not differ between patients with and without greater depressive symptoms. The plasma level of IL-6, but not TNFα, sIL-6R, and IL-1ra, was higher in patients who developed depressive symptoms at 3 months after stroke (median: 4.7 vs 3.4 pg/mL, P = 0.06). Plasma IL-6 predicted the severity of depressive symptoms at 3 months after stroke (β = 0.42, P = 0.03). In conclusion, TLR4-dependent cytokine synthesis was not associated with greater post-stroke depressive symptoms in this study. Circulating IL-6 might be associated with depressive symptoms occurring at 3 months after stroke.

SUBMITTER: Korostynski M

PROVIDER: S-EPMC8076201 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Western diet associated with increased post-stroke depressive symptoms

Project description:The present study examines the association of diet with depressive symptoms among stroke survivors from a community cohort of older adults. Depression is common after stroke. A healthy diet has previously been associated with fewer depressive symptoms in older individuals, but it is unknown if this effect is also seen in stroke survivors. Eighty-six participants from the Memory and Aging Project with a history of stroke at their study baseline enrolment, complete dietary data and two or more assessments for depression were included in this observational prospective cohort analysis. Depressive symptoms were assessed annually with a 10-item version of the Center for Epidemiologic Studies Depression scale. Diet was assessed using a validated food-frequency questionnaire administered at baseline. Diet scores were based on analysis of participants’ reported intakes of 144 food items. A generalised estimating equation (GEE) model was applied to examine the association of diet score with depressive symptoms. The study participants had a mean age of 82 ± 7⋅17 years and 14⋅42 ± 2⋅61 years of education, and 82⋅56 % were female. Western diet score was positively associated with depressive symptoms over time (diet score tertile 3 v. tertile 1: β = 0⋅22, se = 0⋅09, P = 0⋅02; P for trend = 0⋅022). Interaction with sex suggested a stronger effect in females. A Western diet was associated with more post-stroke depressive symptoms, suggesting nutrition is important not only for reducing cerebrovascular risk, but for protecting post-stoke mental health as well.

| S-EPMC9201874 | biostudies-literature

Association between toll-like receptor 4 expression and symptoms of major depressive disorder.

Project description:BackgroundIn our previous study, toll-like receptor 4 (TLR4) mRNA expression level was associated with severity of major depressive disorder (MDD) evaluated with the 17-item Hamilton Depression Rating Scale (HAMD-17). However, there are few studies that have investigated the relationship between symptoms of MDD and changes in TLR4 expression. Therefore, the aim of the present study was to further analyze the association between subscales of HAMD-17 and TLR4.MethodsFifty-one patients with MDD (15 male and 36 female) participated in this study. HAMD-17 was used to assess the symptoms of major depression. The mRNA expression levels of TLR4 were examined in parallel with a housekeeping gene, using real-time polymerase chain reaction. A stepwise linear regression forward model was used to evaluate the relationships between items of HAMD-17 and TLR4 expression.ResultsSome sickness behavior-associated symptoms, including suicide, somatic symptoms of anxiety, or performance of work and activities, were not associated with TLR4 expression. However, psychological signs of anxiety and loss of weight in HAMD-17 can predict the expression level of TLR4.ConclusionOur results suggest a significant association between anxiety, body weight loss, and TLR4 mRNA levels in patients with MDD. Larger longitudinal studies combining both subjective and objective measures of depression are needed to clarify the link between TLR4 and symptoms of depression.

| S-EPMC4525784 | biostudies-literature

Associations of lesion location, structural disconnection, and functional diaschisis with depressive symptoms post stroke.

Project description:IntroductionPost-stroke depressive symptoms (PSDS) are common and relevant for patient outcome, but their complex pathophysiology is ill understood. It likely involves social, psychological and biological factors. Lesion location is a readily available information in stroke patients, but it is unclear if the neurobiological substrates of PSDS are spatially localized. Building on previous analyses, we sought to determine if PSDS are associated with specific lesion locations, structural disconnection and/or localized functional diaschisis.MethodsIn a prospective observational study, we examined 270 patients with first-ever stroke with the Hospital Anxiety and Depression Scale (HADS) around 6 months post-stroke. Based on individual lesion locations and the depression subscale of the HADS we performed support vector regression lesion-symptom mapping, structural-disconnection-symptom mapping and functional lesion network-symptom-mapping, in a reanalysis of this previously published cohort to infer structure-function relationships.ResultsWe found that depressive symptoms were associated with (i) lesions in the right insula, right putamen, inferior frontal gyrus and right amygdala and (ii) structural disconnection in the right temporal lobe. In contrast, we found no association with localized functional diaschisis. In addition, we were unable to confirm a previously described association between depressive symptom load and a network damage score derived from functional disconnection maps.DiscussionBased on our results, and other recent lesion studies, we see growing evidence for a prominent role of right frontostriatal brain circuits in PSDS.

| S-EPMC10231644 | biostudies-literature

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| S-EPMC3031083 | biostudies-literature

Ontogeny of Toll-like receptor mediated cytokine responses of human blood mononuclear cells.

Project description:Newborns and young infants suffer increased infectious morbidity and mortality as compared to older children and adults. Morbidity and mortality due to infection are highest during the first weeks of life, decreasing over several years. Furthermore, most vaccines are not administered around birth, but over the first few years of life. A more complete understanding of the ontogeny of the immune system over the first years of life is thus urgently needed. Here, we applied the most comprehensive analysis focused on the innate immune response following TLR stimulation over the first 2 years of life in the largest such longitudinal cohort studied to-date (35 subjects). We found that innate TLR responses (i) known to support Th17 adaptive immune responses (IL-23, IL-6) peaked around birth and declined over the following 2 years only to increase again by adulthood; (ii) potentially supporting antiviral defense (IFN-?) reached adult level function by 1 year of age; (iii) known to support Th1 type immunity (IL-12p70, IFN-?) slowly rose from a low at birth but remained far below adult responses even at 2 years of age; (iv) inducing IL-10 production steadily declined from a high around birth to adult levels by 1 or 2 years of age, and; (v) leading to production of TNF-? or IL-1? varied by stimuli. Our data contradict the notion of a linear progression from an 'immature' neonatal to a 'mature' adult pattern, but instead indicate the existence of qualitative and quantitative age-specific changes in innate immune reactivity in response to TLR stimulation.

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Project description:The global burden of neonatal and infant mortality due to infection is staggering, particularly in resource-poor settings. Early childhood vaccination is one of the major interventions that can reduce this burden, but there are specific limitations to inducing effective immunity in early life, including impaired neonatal leukocyte production of Th1-polarizing cytokines to many stimuli. Characterizing the ontogeny of Toll-like receptor (TLR)-mediated innate immune responses in infants may shed light on susceptibility to infection in this vulnerable age group, and provide insights into TLR agonists as candidate adjuvants for improved neonatal vaccines. As little is known about the leukocyte responses of infants in resource-poor settings, we characterized production of Th1-, Th2-, and anti-inflammatory-cytokines in response to agonists of TLRs 1-9 in whole blood from 120 Gambian infants ranging from newborns (cord blood) to 12 months of age. Most of the TLR agonists induced TNF?, IL-1?, IL-6, and IL-10 in cord blood. The greatest TNF? responses were observed for TLR4, -5, and -8 agonists, the highest being the thiazoloquinoline CLO75 (TLR7/8) that also uniquely induced cord blood IFN? production. For most agonists, TLR-mediated TNF? and IFN? responses increased from birth to 1 month of age. TLR8 agonists also induced the greatest production of the Th1-polarizing cytokines TNF? and IFN? throughout the first year of life, although the relative responses to the single TLR8 agonist and the combined TLR7/8 agonist changed with age. In contrast, IL-1?, IL-6, and IL-10 responses to most agonists were robust at birth and remained stable through 12 months of age. These observations provide fresh insights into the ontogeny of innate immunity in African children, and may inform development of age-specific adjuvanted vaccine formulations important for global health.

| S-EPMC3076452 | biostudies-literature

Depressive symptoms in caregivers immediately after stroke.

Project description:BACKGROUND:Caregivers of stroke survivors often suffer depressive symptoms that interfere with their own health. Early recognition may lead to attenuation of symptoms and better health and well-being for caregivers. OBJECTIVE:We examined characteristics of caregivers and stroke survivors associated with caregivers' depressive symptoms in the early poststroke period. METHODS:We conducted a prospective, longitudinal exploratory observational study with a convenience sample of 63 caregivers of older adult (≥ 65 years) stroke survivors recruited from urban acute-care settings. We enrolled caregivers by 2 weeks poststroke (T1) and revisited them 4 weeks later (T2). Depressive symptoms were measured using the Patient Health Questionnaire-9. A separate unadjusted linear mixed model was computed to explore significant associations between each caregiver or stroke-survivor characteristic and depressive symptoms. RESULTS:Caregivers, on average, reported mild depressive symptoms at T1 and T2. Each of the following characteristics was independently associated with caregiver depressive symptoms over the first 6 weeks poststroke: caregiver uncertainty (p < 0.001), perceived stress (p < 0.001) but not cortisol levels (p = 0.858 on waking, p = 0.231 evening), coping (p < 0.001), social support (p = 0.006), race (p = 0.022), income (p = 0.001), time spent on care (p = 0.039), and stroke-survivor race (p = 0.033) and functional status (p = 0.003). At T2, caregiver depressive symptoms were correlated with evening cortisol level (p = 0.001). CONCLUSIONS:Caregiver and stroke-survivor characteristics may help identify caregivers at highest risk for early depressive symptoms and guide interventions aimed at their resolution.

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| S-EPMC3257941 | biostudies-literature

Attenuated palmitoylation of serotonin receptor 5-HT1A in brain affects receptor functions and triggers depressive symptoms

Project description:The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are critically implicated in major depressive disorder (MDD), although underlying mechanisms remain enigmatic. Here we demonstrated that 5-HT1AR is palmitoylated in human and rodent brains and identified ZDHHC21 as a major palmitoyl-transferase, whose depletion reduced palmitoylation and consequently signaling functions of 5-HT1AR. Two rodent models for depression show reduced brain ZDHHC21 expression in conjunction with attenuated 5-HT1AR palmitoylation. Moreover, selective knock-down of ZDHHC21 in murine forebrain by itself sufficed to provoke depressive symptoms, demonstrating a causal relationship between 5-HT1AR palmitoylation and depression. Regarding the underlying mechanism, we identified the microRNA miR-30e as a negative regulator of Zdhhc21 expression. By analysis of the post-mortem samples from suicide MDD victims we also found ZDHHC21 expression as well as palmitoylation of 5-HT1AR to be specifically reduced within the prefrontal cortex (PFC), a brain area critically involved in the pathogenesis of depressive symptoms. Our study provides evidence for transcriptional downregulation of 5-HT1AR palmitoylation as a central mechanism in the etiology of depression and even suicide, in effect making the restoration of 5-HT1AR palmitoylation a promising clinical strategy for the treatment of major depressive disorder.

2019-07-16 | PXD012736 | Pride

14-3-3? and 14-3-3? inhibit Toll-like receptor (TLR)-mediated proinflammatory cytokine induction.

Project description:Toll-like receptors (TLRs) are a group of pattern recognition receptors that play a crucial role in the induction of the innate immune response against bacterial and viral infections. TLR3 has emerged as a key sensor of viral double-stranded RNA. Thus, a clearer understanding of the biological processes that modulate TLR3 signaling is essential. Limited studies have applied proteomics toward understanding the dynamics of TLR signaling. Herein, a proteomics approach identified 14-3-3? and 14-3-3? proteins as new members of the TLR signaling complex. Toward the functional characterization of 14-3-3? and 14-3-3? in TLR signaling, we have shown that both of these proteins impair TLR2, TLR3, TLR4, TLR7/8, and TLR9 ligand-induced IL-6, TNF?, and IFN-? production. We also show that 14-3-3? and 14-3-3? impair TLR2-, TLR3-, TLR4-, TLR7/8-, and TLR9-mediated NF-?B and IFN-? reporter gene activity. Interestingly, although the 14-3-3 proteins inhibit poly(I:C)-mediated RANTES production, 14-3-3 proteins augment Pam(3)CSK(4), LPS, R848, and CpG-mediated production of RANTES (regulated on activation normal T cell expressed and secreted) in a Mal (MyD88 adaptor-like)/MyD88-dependent manner. 14-3-3? and 14-3-3? also bind to the TLR adaptors and to both TRAF3 and TRAF6. Our study conclusively shows that 14-3-3? and 14-3-3? play a major regulatory role in balancing the host inflammatory response to viral and bacterial infections through modulation of the TLR signaling pathway. Thus, manipulation of 14-3-3 proteins may represent novel therapeutic targets for inflammatory conditions and infections.

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