Cumulative meta-analysis of interleukins 6 and 1ß, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder.

Cumulative meta-analyses are used to evaluate the extent to which further studies are needed to confirm or refute a hypothesis. We used this approach to assess observational evidence on systemic inflammation in individuals with major depressive disorder. We identified 58 studies of four common inflammatory markers in a literature search of PubMed, Embase and PsychInfo databases in May 2014. Pooled data from the earliest eight studies already showed an association between interleukin-6 concentrations and major depression; 23 more recent studies confirmed this finding (d=0.54, p<0.0001). A significant association between C-reactive protein levels and major depression was noted after 14 studies and this did not change after addition of six more studies (d=0.47, p<0.0001). For these two inflammatory markers, there was moderate heterogeneity in study-specific estimates, subgroup differences were small, and publication bias appeared to be an unlikely explanation for the findings. Sensitivity analyses including only high-quality studies and subjects free of antidepressant medication further verified the associations. While there was a link between tumour necrosis factor-α levels and major depression (d=0.40, p=0.002), the cumulative effect remained uncertain due to the extensive heterogeneity in study-specific estimates and inconsistencies between subgroups. No evidence was found for the association between interleukin-1ß levels and major depression (d=-0.05, p=0.86). In conclusion, this cumulative meta-analysis confirmed higher mean levels of interleukin-6 and C-reactive protein in patients with major depression compared to non-depressed controls. No consistent association between tumour necrosis factor-α, interleukin-1ß and major depression was observed. Future studies should clarify the specific immune mechanisms involved as well as continue testing anti-inflammatory therapies in patients suffering from major depression.

Study protocol: The Whitehall II imaging sub-study.

BACKGROUND: The Whitehall II (WHII) study of British civil servants provides a unique source of longitudinal data to investigate key factors hypothesized to affect brain health and cognitive ageing. This paper introduces the multi-modal magnetic resonance imaging (MRI) protocol and cognitive assessment designed to investigate brain health in a random sample of 800 members of the WHII study. METHODS/DESIGN: A total of 6035 civil servants participated in the WHII Phase 11 clinical examination in 2012-2013. A random sample of these participants was included in a sub-study comprising an MRI brain scan, a detailed clinical and cognitive assessment, and collection of blood and buccal mucosal samples for the characterisation of immune function and associated measures. Data collection for this sub-study started in 2012 and will be completed by 2016. The participants, for whom social and health records have been collected since 1985, were between 60-85 years of age at the time the MRI study started. Here, we describe the pre-specified clinical and cognitive assessment protocols, the state-of-the-art MRI sequences and latest pipelines for analyses of this sub-study. DISCUSSION: The integration of cutting-edge MRI techniques, clinical and cognitive tests in combination with retrospective data on social, behavioural and biological variables during the preceding 25 years from a well-established longitudinal epidemiological study (WHII cohort) will provide a unique opportunity to examine brain structure and function in relation to age-related diseases and the modifiable and non-modifiable factors affecting resilience against and vulnerability to adverse brain changes.

Intradermal cytosine-phosphate-guanosine treatment reduces lung inflammation but induces IFN-γ-mediated airway hyperreactivity in a murine model of natural rubber latex allergy.

Asthma and other allergic diseases are continuously increasing, causing considerable economic and sociologic burden to society. The hygiene hypothesis proposes that lack of microbial T helper (Th) 1-like stimulation during early childhood leads to increased Th2-driven allergic disorders later in life. Immunostimulatory cytosine-phosphate-guanosine (CpG)-oligodeoxynucleotide motifs are candidate molecules for immunotherapeutic studies, as they have been shown to shift the Th2 response toward the Th1 direction and reduce allergic symptoms. Using natural rubber latex (NRL)-induced murine model of asthma, we demonstrated that intradermal CpG administration with allergen reduced pulmonary eosinophilia, mucus production, and Th2-type cytokines, but unexpectedly induced airway hyperreactivity (AHR) to inhaled methacholine, one of the hallmarks of asthma. We found that induction in AHR was dependent on STAT4, but independent of STAT6 signaling. CpG treatment increased production of IFN-γ in the airways and shifted the ratio of CD4(+):CD8(+) T cells toward CD8(+) dominance. By blocking soluble IFN-γ with neutralizing antibody, AHR diminished and the CD4(+):CD8(+) ratio returned to CD4(+) dominance. These results indicate that increased production of IFN-γ in the lungs may lead to severe side effects, such as enhancement of bronchial hyperreactivity to inhaled allergen. This finding should be taken into consideration when planning prophylaxis treatment of asthma with intradermal CpG injections.

Peripheral DNA methylation, cognitive decline and brain aging: pilot findings from the Whitehall II imaging study.

AIM: The present study investigated the link between peripheral DNA methylation (DNAm), cognitive impairment and brain aging. METHODS: We tested the association between blood genome-wide DNAm profiles using the Illumina 450K arrays, cognitive dysfunction and brain MRI measures in selected participants of the Whitehall II imaging sub-study. RESULTS: Eight differentially methylated regions were associated with cognitive impairment. Accelerated aging based on the Hannum epigenetic clock was associated with mean diffusivity and global fractional anisotropy. We also identified modules of co-methylated loci associated with white matter hyperintensities. These co-methylation modules were enriched among pathways relevant to ß-amyloid processing and glutamatergic signaling. CONCLUSION: Our data support the notion that blood DNAm changes may have utility as a biomarker for cognitive dysfunction and brain aging.

Association of circulating metabolites with healthy diet and risk of cardiovascular disease: analysis of two cohort studies.

Diet may modify metabolomic profiles towards higher or lower cardiovascular disease (CVD) risk. We aimed to identify metabolite profiles associated with high adherence to dietary recommendations - the Alternative Healthy Eating Index (AHEI) - and the extent to which metabolites associated with AHEI also predict incident CVD. Relations between AHEI score and 80 circulating lipids and metabolites, quantified by nuclear magnetic resonance metabolomics, were examined using linear regression models in the Whitehall II study (n = 4824, 55.9 ± 6.1 years, 28.0% women) and were replicated in the Cardiovascular Risk in Young Finns Study (n = 1716, 37.7 ± 5.0 years, 56.3% women). We used Cox models to study associations between metabolites and incident CVD over the 15.8-year follow-up in the Whitehall II study. After adjustment for confounders, higher AHEI score (indicating healthier diet) was associated with higher degree of unsaturation of fatty acids (FA) and higher ratios of polyunsaturated FA, omega-3 and docosahexaenoic acid relative to total FA in both Whitehall II and Young Finns studies. A concordance of associations of metabolites with higher AHEI score and lower CVD risk was observed in Whitehall II. Adherence to healthy diet seems to be associated with specific FA that reduce risk of CVD.

Immunomodulatory effects of oak dust exposure in a murine model of allergic asthma.

Repeated airway exposure to wood dust has been reported to cause adverse respiratory effects such as asthma and chronic bronchitis. In our recent study, we found that exposure of mice to oak dust induced more vigorous lung inflammation compared to birch dust exposure. In the present study, we assessed the immunomodulatory effects of repeated intranasal exposure to oak dust both in nonallergic and in ovalbumin-sensitized, allergic mice. Allergen-induced influx of eosinophils and lymphocytes was seen in the lungs of allergic mice. Oak dust exposure elicited infiltration of neutrophils, lymphocytes, and macrophages in nonallergic mice. Interestingly, oak dust-induced lung neutrophilia as well as oak dust-induced production of the proinflammatory cytokine TNF-alpha and chemokine CCL3 were significantly suppressed in allergic mice. On the other hand, allergen-induced expression of IL-13 mRNA and protein was significantly reduced in oak dust-exposed allergic mice. Finally, allergen-induced airway hyperreactivity to inhaled metacholine was significantly suppressed in oak dust-exposed allergic mice. The present results suggest that repeated airway exposure to oak dust can regulate pulmonary inflammation and airway responses depending on the immunological status of the animal.

Mechanisms of particle-induced pulmonary inflammation in a mouse model: exposure to wood dust.

Repeated airway exposure to wood dust has long been known to cause adverse respiratory effects such as asthma and chronic bronchitis and impairment of lung function. However, the mechanisms underlying the inflammatory responses of the airways after wood dust exposure are poorly known. We used a mouse model to elucidate the mechanisms of particle-induced inflammatory responses to fine wood dust particles. BALB/c mice were exposed to intranasally administered fine (more than 99% of the particles had a particle size of < or = 5 microm, with virtually identical size distribution) birch or oak dusts twice a week for 3 weeks. PBS, LPS, and titanium dioxide were used as controls. Intranasal instillation of birch or oak dusts elicited influx of inflammatory cells to the lungs in mice. Enhancement of lymphocytes and neutrophils was seen after oak dust exposure, whereas eosinophil infiltration was higher after birch dust exposure. Infiltration of inflammatory cells was associated with an increase in the mRNA levels of several cytokines, chemokines, and chemokine receptors in lung tissue. Oak dust appeared to be a more potent inducer of these inflammatory mediators than birch dust. The results from our in vivo mouse model show that repeated airway exposure to wood dust can elicit lung inflammation, which is accompanied by induction of several proinflammatory cytokines and chemokines. Oak and birch dusts exhibited quantitative and qualitative differences in the elicitation of pulmonary inflammation, suggesting that the inflammatory responses induced by the wood species may rise via different cellular mechanisms.

Innate and adaptive immunity in the development of depression: An update on current knowledge and technological advances.

The inflammation theory of depression, proposed over 20years ago, was influenced by early studies on T cell responses and since then has been a stimulus for numerous research projects aimed at understanding the relationship between immune function and depression. Observational studies have shown that indicators of immunity, especially C reactive protein and proinflammatory cytokines, such as interleukin 6, are associated with an increased risk of depressive disorders, although the evidence from randomized trials remains limited and only few studies have assessed the interplay between innate and adaptive immunity in depression. In this paper, we review current knowledge on the interactions between central and peripheral innate and adaptive immune molecules and the potential role of immune-related activation of microglia, inflammasomes and indoleamine-2,3-dioxygenase in the development of depressive symptoms. We highlight how combining basic immune methods with more advanced 'omics' technologies would help us to make progress in unravelling the complex associations between altered immune function and depressive disorders, in the identification of depression-specific biomarkers and in developing immunotherapeutic treatment strategies that take individual variability into account.

Biomarkers of subclinical inflammation and increases in glycaemia, insulin resistance and beta-cell function in non-diabetic individuals: the Whitehall II study.

OBJECTIVE: Higher systemic levels of pro-inflammatory biomarkers and low adiponectin are associated with increased risk of type 2 diabetes, but their associations with changes in glycaemic deterioration before onset of diabetes are poorly understood. We aimed to study whether inflammation-related biomarkers are associated with 5-year changes in glucose and insulin, HbA1c, insulin sensitivity and beta-cell function before the diagnosis of type 2 diabetes and whether these associations may be bidirectional. DESIGN AND METHODS: We used multiple repeat measures (17 891 person-examinations from 7683 non-diabetic participants) from the Whitehall II study to assess whether circulating high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6), IL1 receptor antagonist (IL1Ra) and adiponectin are associated with subsequent changes in glycaemia, insulin, insulin resistance and beta-cell function (based on oral glucose tolerance tests). We examined bidirectionality by testing if parameters of glucose metabolism at baseline are associated with changes in inflammation-related biomarkers. RESULTS: Higher hsCRP and IL6 were associated with increases in fasting insulin, insulin resistance and, for IL6, with beta-cell function after adjustment for confounders. Higher adiponectin was associated with decreases in fasting glucose, HbA1c, fasting insulin, insulin resistance and beta-cell function. The reverse approach showed that 2-h glucose and insulin sensitivity were associated with changes in IL1Ra. Fasting insulin and insulin resistance showed inverse associations with changes in adiponectin. CONCLUSIONS: Subclinical inflammation is associated with development of increased glycaemia, insulin resistance and beta-cell function in non-diabetic individuals. These findings are consistent with the hypothesis that inflammation-related processes may increase insulin resistance and lead to a compensatory upregulation of beta-cell function.

Cutaneous, but not airway, latex exposure induces allergic lung inflammation and airway hyperreactivity in mice.

As respiratory symptoms are common in addition to skin reactions in natural rubber latex allergy, we investigated the significance of different allergen exposure routes in the development of lung inflammation and airway hyperreactivity (AHR). Both intracutaneous (IC) and intraperitoneal (IP) exposure followed by airway challenge with latex proteins induced an influx of mononuclear cells and eosinophils to the lungs. AHR and lung mucus production increased significantly after IC and IP but not after intranasal (IN) exposure. Infiltration of inflammatory cells was associated with the induction of T-helper type 2 (Th2) cytokines and several CC chemokines. Only a marginal induction of these mediators was found after IN exposure. On the contrary, increased levels of transforming growth factor-beta1 and forkhead box 3 mRNA, markers of regulatory activities, were found in the lungs after IN but not after IC exposure. Finally, IC and IP, but not IN, latex exposure induced a striking increase in specific immunoglobulin E (IgE) levels. Cutaneous latex exposure in the absence of adjuvant followed by airway challenge induces a local Th2-dominated lung inflammation and a systemic IgE response. Cutaneous exposure to proteins eluting from latex products may therefore profoundly contribute to the development of asthma in latex allergy.

Invariant Natural Killer T Cells Play a Role in Chemotaxis, Complement Activation and Mucus Production in a Mouse Model of Airway Hyperreactivity and Inflammation.

CD1d-restricted invariant natural killer T (iNKT) cells play a critical role in the induction of airway hyperreactivity (AHR). After intranasal alpha-galactosylceramide (α-GalCer) administration, bronchoalveolar lavage fluid (BALF) proteins from mouse lung were resolved by two-dimensional differential gel electrophoresis (2D-DIGE), and identified by tandem mass spectroscopy. A lack of iNKT cells prevented the development of airway responses including AHR, neutrophilia and the production of the proinflammatory cytokines in lungs. Differentially abundant proteins in the BALF proteome of α-GalCer-treated wild type mice included lungkine (CXCL15), pulmonary surfactant-associated protein D (SFTPD), calcium-activated chloride channel regulator 1 (CLCA1), fragments of complement 3, chitinase 3-like proteins 1 (CH3LI) and 3 (CH3L3) and neutrophil gelatinase-associated lipocalin (NGAL). These proteins may contribute to iNKT regulated AHR via several mechanisms: altering leukocyte chemotaxis, increasing airway mucus production and possibly via complement activation.

Toll-like receptor activation during cutaneous allergen sensitization blocks development of asthma through IFN-gamma-dependent mechanisms.

Toll-like receptors (TLRs) are pattern-recognition receptors that have a pivotal role as primary sensors of microbial products and as initiators of innate and adaptive immune responses. We investigated the role of TLR2, TLR3, and TLR4 activation during cutaneous allergen sensitization in the modulation of allergic asthma. The results show that dermal exposure to TLR4 ligand lipopolysaccharide (LPS) or TLR2 ligand Pam3Cys suppresses asthmatic responses by reducing airway hyperreactivity, mucus production, Th2-type inflammation in the lungs, and IgE antibodies in serum in a dose-dependent manner. In contrast, TLR3 ligand Poly(I:C) did not protect the mice from asthmatic symptoms but reduced IgE and induced IgG2a in serum. LPS (especially) and Pam3Cys enhanced the activation of dermal dendritic cell (DCs) by increasing the expression of CD80 and CD86 but decreased DC numbers in draining lymph nodes at early time points. Later, these changes in DCs led to an increased number of CD8(+) T cells and enhanced the production of IFN-γ in bronchoalveolar lavage fluid. In conclusion, dermal exposure to LPS during sensitization modulates the asthmatic response by skewing the Th1/Th2 balance toward Th1 by stimulating the production of IFN-γ. These findings support the hygiene hypothesis and pinpoint the importance of dermal microbiome in the development of allergy and asthma.

ST2 regulates allergic airway inflammation and T-cell polarization in epicutaneously sensitized mice.

IL-33 is an inducer of proinflammatory and T-helper type 2 (Th2) cytokines, which have an important role in atopic dermatitis (AD) and allergic asthma. ST2 is a specific receptor for IL-33 and is expressed on Th2 cells, eosinophils and mast cells. A murine model of AD was used to characterize the role of ST2 in allergen-induced skin inflammation and allergic asthma. ST2-/- and wild-type (WT) mice were epicutaneously sensitized with ovalbumin (OVA) and staphylococcal enterotoxin B, and intranasally challenged with OVA. ST2-/- mice exhibited increased production of IFNγ and increased number of CD8(+) T cells in the sensitized skin and in the airways compared with WT mice. The number of eosinophils was decreased, and Th2 cytokines were downregulated in the airways of epicutaneously sensitized ST2-/- mice compared with WT controls. However, dermal eosinophil numbers were as in WT, and the levels of Th2 cytokines were even elevated in the sensitized skin of ST2-/- mice. ST2-/- mice had elevated numbers of neutrophils and macrophages and increased levels of proinflammatory cytokines in the sensitized skin. The role of ST2 differs between different target tissues: ST2 is dispensable for the development of Th2 response in the sensitized skin, whereas it is a main inducer of Th2 cytokines in asthmatic airways.

Assessment of the neuropeptide S system in anxiety disorders.

BACKGROUND: The G protein-coupled receptor neuropeptide S receptor 1 (NPSR1) and its ligand neuropeptide S (NPS) form a signaling system mainly implicated in susceptibility to asthma and inflammatory disorders in humans and regulation of anxiety and arousal in rodents. We addressed here the role of NPS and NPSR1 as susceptibility genes for human anxiety disorders. METHODS: We performed comprehensive association analysis of genetic variants in NPS and NPSR1 in three independent study samples. We first studied a population-based sample (Health 2000, Finland) of 321 anxiety disorder patients and 1317 control subjects and subsequently a Spanish clinical panic disorder sample consisting of 188 cases and 315 control subjects. In addition, we examined a birth cohort of 2020 children (Barn Allergi Miljö Stockholm Epidemiologi [BAMSE], Sweden). We then tested whether alleles of the most significantly associated single nucleotide polymorphisms alter DNA-protein complex formation in electrophoretic mobility shift assays. Finally, we compared acute stress responses on the gene expression level in wild-type and Npsr1(-/-) mice. RESULTS: We confirmed previously observed epidemiological association between anxiety and asthma in two population-based cohorts. Single nucleotide polymorphisms within NPS and NPSR1 associated with panic disorder diagnosis in the Finnish and Spanish samples and with parent-reported anxiety/depression in the BAMSE sample. Moreover, some of the implicated single nucleotide polymorphisms potentially affect transcription factor binding. Expression of neurotrophin-3, a neurotrophic factor connected to stress and panic reaction, was significantly downregulated in brain regions of stressed Npsr1(-/-) mice, whereas interleukin-1 beta, an active stress-related immunotransmitter, was upregulated. CONCLUSIONS: Our results suggest that NPS-NPSR1 signaling is likely involved in anxiety.