Indoleamine 2,3-dioxygenase 1 is upregulated in activated microglia in mice cerebellum during acute viral encephalitis

Taguchi, Azuma; Niwa, Masayuki; Hoshi, Masato; Masutani, Teruaki; Hisamatsu, Kenji; Kobayashi, Kazuhiro; Hatano, Yuichiro; Tomita, Hiroyuki; Hara, Akira

doi:10.1016/j.neulet.2014.01.051

Cited by 16 publications

(14 citation statements)

References 25 publications

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“…Data derived from in vivo studies also indicate that Ido1 is up‐regulated during viral encephalitis. For instance, intraperitoneal injection with encephalomyocarditis virus increased Ido1 expression in the cerebellum, where it colocalized to areas of reactive gliosis . Moreover, peripheral infection with Japanese encephalitis virus (JEV) increased Ido1 expression in the periphery and brain, and Ido1‐KO mice were more resistant to encephalitis .…”

Section: Discussionmentioning

confidence: 99%

Indoleamine 2,3‐dioxygenase 1 deletion promotes Theiler's virus–induced seizures in C57BL/6J mice

et al. 2019

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Summary Objective Viral encephalitis increases the risk for developing seizures and epilepsy. Indoleamine 2,3‐dioxygenase 1 (Ido1) is induced by inflammatory cytokines and functions to metabolize tryptophan to kynurenine. Kynurenine can be further metabolized to produce kynurenic acid and the N‐methyl‐d‐aspartate receptor agonist quinolinic acid (QuinA). In the present study, we sought to determine the role of Ido1 in promoting seizures in an animal model of viral encephalitis. Methods C57BL/6J and Ido1 knockout mice (Ido1‐KO) were infected with Theiler's murine encephalomyelitis virus (TMEV). Quantitative real‐time polymerase chain reaction was used to evaluate hippocampal expression of proinflammatory cytokines, Ido1, and viral RNA. Body weights and seizure scores were recorded daily. Elevated zero maze was used to assess differences in behavior, and hippocampal pathology was determined by immunohistochemistry. Results Infected C57BL/6J mice up‐regulated proinflammatory cytokines, Ido1, and genes encoding the enzymatic cascade responsible for QuinA production in the kynurenine pathway prior to the onset of seizures. Seizure incidence was elevated in Ido1‐KO compared to C57BL/6J mice. Infection increased locomotor activity in Ido1‐KO compared to C57BL/6J mice. Furthermore, the occurrence of seizures was associated with hyperexcitability. Neither expression of proinflammatory cytokines nor viral RNA was altered as a result of genotype. Immunohistochemical analysis revealed increased hippocampal pathology in Ido1‐KO mice. Significance Our findings suggest that Ido1 deletion promotes seizures and neuropathogenesis during acute TMEV encephalitis.

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Section: Discussionmentioning

confidence: 99%

Indoleamine 2,3‐dioxygenase 1 deletion promotes Theiler's virus–induced seizures in C57BL/6J mice

et al. 2019

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“…Thus, IDO1 is up-regulated in vivo following infection with HSV-1 (herpes simplex virus type 1) [531], poliovirus (which causes poliomyelitis) [532], hepatitis C [533,534], dengue virus [535], Epstein-Barr virus (which causes glandular fever) [536], encephalomyocarditis virus (which causes encephalitis and myocarditis primarily in pigs) [537,538], LP-BM5 murine leukaemia virus (murine AIDS) [502], SIV (simian immunodeficiency virus) [539] and HIV [540][541][542][543].…”

Section: Expression Of Ido1 In Vitro and In Vivo In Response To Viralmentioning

confidence: 99%

“…Ido1 gene-deficient mice exhibit reduced LP-BM5 viral load due to an enhanced type I IFN production [502], although a more recent study reports no difference in viral burden between wild-type and IDO1 −/− mice [552]. In encephalomyocarditis virus infection, which induces IDO1 in microglia, Purkinje cells [538], spleen and heart, Ido1 gene deficiency affords milder disease, linked to increased IFNα and IFNβ expression and a corresponding reduced viral load [537]. Administration of Kyn, 3-HAA and 3-HK to IDO1 −/− mice restored disease severity, with these mice exhibiting more severe myocardial damage and succumbing to infection to a greater degree than wild-type mice [537], demonstrating that elevating Kyn metabolites alone significantly exacerbates encephalomyocarditis.…”

Section: Role Of Ido1 In Virus Infection In Vivomentioning

confidence: 99%

Role of indoleamine 2,3-dioxygenase in health and disease

et al. 2015

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IDO1 (indoleamine 2,3-dioxygenase 1) is a member of a unique class of mammalian haem dioxygenases that catalyse the oxidative catabolism of the least-abundant essential amino acid, L-Trp (L-tryptophan), along the kynurenine pathway. Significant increases in knowledge have been recently gained with respect to understanding the fundamental biochemistry of IDO1 including its catalytic reaction mechanism, the scope of enzyme reactions it catalyses, the biochemical mechanisms controlling IDO1 expression and enzyme activity, and the discovery of enzyme inhibitors. Major advances in understanding the roles of IDO1 in physiology and disease have also been realised. IDO1 is recognised as a prominent immune regulatory enzyme capable of modulating immune cell activation status and phenotype via several molecular mechanisms including enzyme-dependent deprivation of L-Trp and its conversion into the aryl hydrocarbon receptor ligand kynurenine and other bioactive kynurenine pathway metabolites, or non-enzymatic cell signalling actions involving tyrosine phosphorylation of IDO1. Through these different modes of biochemical signalling, IDO1 regulates certain physiological functions (e.g. pregnancy) and modulates the pathogenesis and severity of diverse conditions including chronic inflammation, infectious disease, allergic and autoimmune disorders, transplantation, neuropathology and cancer. In the present review, we detail the current understanding of IDO1's catalytic actions and the biochemical mechanisms regulating IDO1 expression and activity. We also discuss the biological functions of IDO1 with a focus on the enzyme's immune-modulatory function, its medical implications in diverse pathological settings and its utility as a therapeutic target.

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“…One shared candidate pathway for the mediation of both SBS and MDD-like behaviors is increased brain pro-inflammatory cytokine levels (for review : Boulanger, 2009;Capuron and Miller, 2011;Miller et al, 2009). A second candidate pathway is altered metabolism of tryptophan (Dantzer et al, 2008;Schwarcz et al, 2012): IFN- and TNF induce expression of indoleamine 2,3 dioxygenase (IDO) (O'Connor et al, 2009a), an intracellular enzyme expressed by dendritic cells, macrophages (periphery) and microglia (brain), that metabolizes tryptophan along the kynurenine (KYN) pathway (for review : Felger and Miller, 2012;Mellor and Munn, 2004;Schwarcz et al, 2012;Taguchi et al, 2014). In the mouse brain, IDO expression is increased at 24-48 hours after LPS treatment, coincident with LPS-induced behavioral effects (O'Connor et al, 2009b).…”

Section: Including Tumor Necrosis Factor (Tnf) Interleukin-(il-) Il-mentioning

confidence: 99%

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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Indoleamine 2,3-dioxygenase 1 is upregulated in activated microglia in mice cerebellum during acute viral encephalitis

Cited by 16 publications

References 25 publications

Indoleamine 2,3‐dioxygenase 1 deletion promotes Theiler's virus–induced seizures in C57BL/6J mice

Indoleamine 2,3‐dioxygenase 1 deletion promotes Theiler's virus–induced seizures in C57BL/6J mice

Role of indoleamine 2,3-dioxygenase in health and disease

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

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