Psychological Stress-Induced, IDO1-Dependent Tryptophan Catabolism: Implications on Immunosuppression in Mice and Humans

Kiank, Cornelia; Zeden, Jan-Philip; Drude, Solveig; Domańska, Grażyna; Fusch, Gerhard; Otten, Winfried; Schuett, Christine

doi:10.1371/journal.pone.0011825

Cited by 105 publications

(113 citation statements)

References 52 publications

(80 reference statements)

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“…Selectivity for IDO1 relative to tryptophan 2, 3-dioxygenase (TDO) (EC 50 TDO: EC 50 IDO1) was 180. These efficacy and selectivity estimates for IDOInh are higher than those reported for 1-methyltryptophan (Hou et al, 2007;Lob et al, 2014), the IDO inhibitor used to-date to study effects of KYN-pathway inhibition (Dobos et al, 2012;Kiank et al, 2010;O'Connor et al, 2009b Naive mice were allocated randomly to four treatment groups: IgG2a-Vehicle (IgG2a-VEH, N=7), IgG2a-IDO inhibitor (IgG2a-IDOInh, N=8), CD40AB-VEH (N=7) and CD40AB-IDOInh (N=8).…”

Section: Cd40ab  Ido Inhibitor On Saccharin Drinking and Levels Of Cmentioning

confidence: 79%

CD40-TNF activation in mice induces extended sickness behavior syndrome co-incident with but not dependent on activation of the kynurenine pathway

Cathomas

Fuertig

Sigrist

et al. 2015

Brain, Behavior, and Immunity

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The similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immune-inflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects co-occurred with increased plasma and brain levels of kynurenine and its metabolites (days 1-7/8). Co-injection of TNF blocker etanercept with CD40AB prevented each of SBS, reduced saccharin drinking, and kynurenine pathway activation in plasma and brain. Repeated oral administration of a selective indoleamine 2,3-dioxygenase (IDO) inhibitor blocked activation of the kynurenine pathway but was without effect on SBS and saccharin drinking. This study provides novel evidence that CD40-TNF activation induces deficits in saccharin drinking and Pavlovian fear learning and activates the kynurenine pathway, and that CD40-TNF activation of the kynurenine pathway is not necessary for induction of the acute or extended SBS effects. AbstractThe similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immuneinflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3 days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects co-occurred with increased plasma and brain levels of kynurenine and its metabolites (days 1-7/8). Co-injection of TNF blocker etanercept with CD40AB prevented each of SBS, reduced saccharin drinking, and kynurenine pathway activation in plasma and brain. Repeated oral administration of a selective indoleamine 2,3-dioxyg...

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Section: Cd40ab  Ido Inhibitor On Saccharin Drinking and Levels Of Cmentioning

confidence: 79%

CD40-TNF activation in mice induces extended sickness behavior syndrome co-incident with but not dependent on activation of the kynurenine pathway

Cathomas

Fuertig

Sigrist

et al. 2015

Brain, Behavior, and Immunity

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“…Rats exposed to repeated physical restraint exhibit increased liver TDO, brain cortex Tdo2 mRNA expression, and plasma KYN (Gibney et al, 2014). Mice exposed to acute acoustic + restraint stress exhibited increased Ido1 mRNA expression in spleen, ileum and brain, dependent on increased plasma TNF- and IFN-, that was apparent at 12 h after stress termination and returned to basal expression after 24 h 28 (Kiank et al, 2010). Whether CSD leads to transient increases in Ido1 expression following the daily attack sessions remains to be investigated.…”

Section: Psychosocial Stress-induced Activation Of the Kynurenine Patmentioning

confidence: 97%

“…Pre-treatment of mice with the competitive IDO inhibitor 1-methyltryptophan (1-MT) decreased the effectseverity of repeated acoustic + restraint stress on physical condition and motor inactivity (Kiank et al, 2010). Pre-treatment with 1-MT prevented systemic LPS, which activates the IDO1-KYN pathway, from decreasing mouse activity in FST and TST (O'Connor et al, 2009b).…”

Section: Integrating Current Findings With Existing Evidence For Kyn-mentioning

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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“…It is also conceivable that psychosocial changes associated with schizophrenia increase psychological stress (Betensky et al, 2008), leading to increased KYN (Kiank et al, 2010), immunosuppression, and reactivation of T. gondii.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Combined Toxoplasma gondii seropositivity and high blood kynurenine – Linked with nonfatal suicidal self-directed violence in patients with schizophrenia

Okusaga

Duncan

Langenberg

et al. 2016

Journal of Psychiatric Research

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Psychological Stress-Induced, IDO1-Dependent Tryptophan Catabolism: Implications on Immunosuppression in Mice and Humans

Cited by 105 publications

References 52 publications

CD40-TNF activation in mice induces extended sickness behavior syndrome co-incident with but not dependent on activation of the kynurenine pathway

CD40-TNF activation in mice induces extended sickness behavior syndrome co-incident with but not dependent on activation of the kynurenine pathway

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

Combined Toxoplasma gondii seropositivity and high blood kynurenine – Linked with nonfatal suicidal self-directed violence in patients with schizophrenia

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