Levels and Determinants of Inflammatory Biomarkers in a Swiss Population-Based Sample (CoLaus Study)

Marques‐Vidal, Pedro; Bochud, Murielle; Bastardot, François; Lüscher, Thomas F.; Ferrero, François; Gaspoz, Jean‐Michel; Paccaud, Fred; Urwyler, Adrian; Känel, Roland von; Hock, Christoph; Waeber, Gérard; Preisig, Martin; Vollenweider, Péter

doi:10.1371/journal.pone.0021002

Cited by 62 publications

(60 citation statements)

References 34 publications

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“…In Expt A, determination of immunoreactive TNF-α in plasma and hippocampus was conducted using a flow cytometric particle based assay with a lower limit of quantification (LLOQ) of 0.5 pg/ml (Azzinnari et al, 2014;Marques-Vidal et al, 2011). For hippocampal TNF-, punches were ultrasonicated in 10x volume of complete Tris lysis buffer, centrifuged, and the supernatant pipetted off for assay.…”

Section: Immunoassay Of Plasma and Brain Pro-inflammatory Cytokinesmentioning

confidence: 99%

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Fuertig

Azzinnari

Bergamini

et al. 2016

Brain, Behavior, and Immunity

115

125

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Psychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immuneinflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity to aversive stimuli. The present mouse study investigated effects of psychosocial stress as chronic social defeat (CSD) versus control-handling (CON) on: Pavlovian tone-shock fear conditioning, activation of the kynurenine pathway, and efficacy of a specific inhibitor (IDOInh) of the tryptophan-kynurenine catabolizing enzyme indoleamine 2,3-dioxygenase (IDO1), in reversing CSD effects on the kynurenine pathway and fear. CSD led to excessive fear learning and memory, whilst repeated oral escitalopram (antidepressant and anxiolytic) reversed excessive fear memory, indicating predictive validity of the model. CSD led to higher blood levels of TNF-, IFN-, kynurenine (KYN), 3-hydroxykynurenine (3-HK) and kynurenic acid, higher KYN and 3-HK in amygdala and hippocampus. However, CSD was without effect on IDO1 gene or protein expression in spleen, ileum and liver, whilst increasing liver TDO2 gene expression. Nonetheless, oral IDOInh reduced blood and brain levels of KYN and 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyper-activity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders. ABSTRACTPsychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immune-inflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyperactivity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders.3

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Section: Immunoassay Of Plasma and Brain Pro-inflammatory Cytokinesmentioning

confidence: 99%

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Fuertig

Azzinnari

Bergamini

et al. 2016

Brain, Behavior, and Immunity

115

125

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“…Plasma proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6) were measured using a multiplexed particle-based flow cytometric cytokine assay (Marques-Vidal et al, 2011). The lower limit of detection for TNF and IL-6 was 0.5 pg/mL.…”

Section: Plasma Cytokine Measurementmentioning

confidence: 99%

Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function

et al. 2014

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In neuropsychiatry, animal studies demonstrating causal effects of environmental manipulations relevant to human aetiology on behaviours relevant to human psychopathologies are valuable. Such valid models can improve understanding of aetio-pathophysiology and preclinical discovery and development of new treatments. In depression, specific uncontrollable stressful life events are major aetiological factors, and subsequent generalized increases in fearfulness, helplessness and fatigue are core symptoms or features. Here we exposed adult male C57BL/6 mice to 15-day psychosocial stress with loss of social control but minimal physical wounding. One cohort was assessed in a 3-day test paradigm of motor activity, fear conditioning and 2-way avoid-escape behaviour on days 16-18, and a second cohort was assessed in a treadmill fatigue paradigm on days 19 and 29, followed by the 3-day paradigm on days 30-32. All tests used a physical aversive stimulus, namely mild, brief electroshocks. Socially stressed mice displayed decreased motor activity, increased fear acquisition, decreased 2-way avoid-escape responding (increased helplessness) and increased fatigue. They also displayed increased plasma TNF and spleen hypertrophy, and adrenal hypertrophy without hyper-corticoidism. In a third cohort, psychosocial stress effects on brain gene expression were assessed using next generation sequencing. Gene expression was altered in pathways of inflammation and G-protein coupled receptors in prefrontal cortex and amygdala; in the latter, expression of genes important in dopamine function were de-regulated including down-regulated Drd2, Adora2a and Darpp-32. This model can be applied to identify targets for treating psychopathologies such as helplessness or fatigue, and to screen compounds/biologics developed to act at these targets. AbstractIn neuropsychiatric research, animal studies that demonstrate causal effects of environmental manipulations relevant to human aetiological factors on emotional and cognitive behaviours relevant to human psychopathologies are valuable. Such valid animal models can be useful for improved understanding of aetio-pathophysiology and preclinical discovery and development of new treatments. In depression, specific uncontrollable stressful life events are major aetiological factors, and subsequent generalized increases in fearfulness, helplessness and fatigue are core psychopathology symptoms or features. In the present study we exposed adult male C57BL/6 mice to an environmental manipulation of 15-day psychosocial stress with loss of social control but with minimal physical wounding. One cohort of stressed and control mice was assessed in a novel 3-day test paradigm of motor activity, fear conditioning and 2-way avoid-escape behaviour on days 16-18, and a second cohort was assessed in a treadmill fatigue paradigm on days 19 and 29, followed by the 3-day paradigm on days 30-32. All tests used a physical aversive stimulus, namely mild, brief electroshocks. The socially stressed mice displayed dec...

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“…In plasma samples, the concentrations of murine TNF, IL-6 and IL-10 were determined using a multiplexed particle-based flow cytometric cytokine assay according to a published procedure (Marques-Vidal et al, 2011;Cathomas et al, 2015). For TNF, the range of the standard curve was 0.1-30 pg/ml, and the lower limit of quantification (LLOQ) was 0.3 pg/ml.…”

Section: Plasma and Brain-tissue Cytokine Immunoassaymentioning

confidence: 99%

Differential effects of peripheral and brain tumor necrosis factor on inflammation, sickness, emotional behavior and memory in mice

Klaus

Paterna

Marzorati

et al. 2016

Brain, Behavior, and Immunity

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Tumor necrosis factor alpha (TNF) is increased in depression and clinical-trial evidence indicates that blocking peripheral TNF has some antidepressant efficacy. In rodents, peripheral or intracerebroventricular TNF results in sickness e.g. reduced body weight, altered emotional behavior and impaired memory. However, the underlying pathways and responsible brain regions are poorly understood. The aim of this mouse study was to increase understanding by comparing the effects of sustained increases in TNF in the circulation, in brain regions impacted by increased circulating TNF, or specific brain regions. Increased peripheral TNF achieved by repeated daily injection (IP-TNF) or osmotic pump resulted in decreased body weight, decreased saccharin (reward) consumption, and increased memory of an aversive conditioned stimulus. These effects co-occurred with increased plasma interleukin-6 and increased IPderived TNF in brain peri-ventricular regions. An adenovirus-associated viral TNF vector (AAV-TNF) was constructed, brain injection of which resulted in dose-dependent, sustained and region-specific TNF expression, and was without effect on blood cytokine levels. Lateral ventricle AAV-TNF yielded increased TNF in the same brain regions as IP-TNF. In contrast to IP-TNF it was without effect on body weight, saccharin consumption and fear memory, although it did increase anxiety. Hippocampal AAV-TNF led to decreased body weight. It increased conditioning to but not subsequent memory of an aversive context, suggesting impaired consolidation; it also increased anxiety. Amygdala AAV-TNF was without effect on body weight and aversive stimulus learning-memory, but reduced saccharin consumption and increased anxiety. This study adds significantly to the evidence that both peripheral and brain region-specific increases in TNF lead to both sickness and depression-and anxiety disorder-relevant behavior and do so via different pathways. It thereby highlights the complexity in terms of indirect and direct pathways via which increased TNF can act and which need to be taken into account when considering it as a therapeutic target. AbstractTumor necrosis factor alpha (TNF) is increased in depression and clinical-trial evidence indicates that blocking peripheral TNF has some antidepressant efficacy. In rodents, peripheral or intracerebroventricular TNF results in sickness e.g. reduced body weight, altered emotional behavior and impaired memory. However, the underlying pathways and responsible brain regions are poorly understood. The aim of this mouse study was to increase understanding by comparing the effects of sustained increases in TNF in the circulation, in brain regions impacted by increased circulating TNF, or specific brain regions.Increased peripheral TNF achieved by repeated daily injection (IP-TNF) or osmotic pump resulted in decreased body weight, decreased saccharin (reward) consumption, and increased memory of an aversive conditioned. These effects co-occurred with increased plasma interleukin-6 and increased I...

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Levels and Determinants of Inflammatory Biomarkers in a Swiss Population-Based Sample (CoLaus Study)

Cited by 62 publications

References 34 publications

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function

Differential effects of peripheral and brain tumor necrosis factor on inflammation, sickness, emotional behavior and memory in mice

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