scholarly journals Role of the indoleamine-2,3-dioxygenase/kynurenine pathway of tryptophan metabolism in behavioral alterations in a hepatic encephalopathy rat model

2018 ◽  
Vol 15 (1) ◽  
Author(s):  
Xi Jiang ◽  
Lexing Xu ◽  
Lin Tang ◽  
Fuhe Liu ◽  
Ziwei Chen ◽  
...  
Keyword(s):  
Hepatic Encephalopathy ◽  
Rat Model ◽  
Kynurenine Pathway ◽  
Tryptophan Metabolism ◽  
Behavioral Alterations ◽  
Indoleamine 2,3 Dioxygenase

scholarly journals Indoleamine 2,3-Dioxygenase 2 Deficiency Exacerbates Imiquimod-Induced Psoriasis-Like Skin Inflammation

2020 ◽  
Vol 21 (15) ◽  
pp. 5515
Author(s):  
Kento Fujii ◽  
Yasuko Yamamoto ◽  
Yoko Mizutani ◽  
Kuniaki Saito ◽  
Mariko Seishima
Keyword(s):  
Immune Responses ◽  
Immune Cells ◽  
Skin Inflammation ◽  
Kynurenine Pathway ◽  
Immune Functions ◽  
Wild Type ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tnf Α ◽  
In The Wild

Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme known to suppress immune responses, and several reports have showed that it is associated with psoriasis. IDO2 is an isoform of IDO1, recently identified as a catalytic enzyme in the tryptophan-kynurenine pathway, which is expressed in dendritic cells and monocytes. The expression of IDO2 in immune cells suggests that IDO2 may contribute to immune functions. However, the role of IDO2 in the pathogenesis of psoriasis remains unclear. In this study, to elucidate the role of IDO2 in psoriasis, we assessed imiquimod (IMQ)-induced psoriasis-like dermatitis in IDO2 knockout (KO) mice. Skin inflammation, evaluated by scoring erythema, scaling, and ear thickness, was significantly worse in the IDO2 KO mice than in the wild-type (WT) mice. The mRNA expression levels of TNF-α, IL-23p19, and IL-17A, key cytokines involved in the development of psoriasis, were also increased in the IDO2 KO mice. Furthermore, immunohistochemistry revealed that the number of Ki67-positive cells in the epidermis and CD4-, CD8-, and IL-17-positive lymphocytes infiltrating the dermis were significantly increased in the IDO2 KO mice. These results suggest that IDO2 might decrease IL-17 expression, thereby resulting in the suppression of skin inflammation in IMQ-induced psoriasis-like dermatitis.

Decreased levels of kynurenic acid in prefrontal cortex in a genetic animal model of depression

2016 ◽  
Vol 29 (1) ◽  
pp. 54-58 ◽  
Author(s):  
Xi-Cong Liu ◽  
Sophie Erhardt ◽  
Michel Goiny ◽  
Göran Engberg ◽  
Aleksander A. Mathé
Keyword(s):  
Prefrontal Cortex ◽  
Rat Model ◽  
High Performance ◽  
Kynurenic Acid ◽  
Kynurenine Pathway ◽  
Genetic Animal Model ◽  
Animal Model Of Depression ◽  
Tryptophan Metabolites ◽  
Sensitive Line

ObjectiveThere is a growing interest in the role of kynurenine pathway and tryptophan metabolites in the pathophysiology of depression. In the present study, the metabolism of tryptophan along the kynurenine pathway was analysed in a rat model of depression.MethodsKynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK) were measured by high-performance liquid chromatography (HPLC) in prefrontal cortex (PFC) and frontal cortex (FC) in a rat model of depression, the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL) rats. In addition, KYNA was also measured in hippocampus, striatum and cerebellum.ResultsKYNA levels were reduced in the PFC of FSL rats compared with FRL rats, but did not differ with regard to the FC, hippocampus, striatum or cerebellum. 3-HK levels in PFC and FC, representing the activity of the microglial branch of the kynurenine pathway, did not differ between the FSL and FRL strains.ConclusionOur results suggest an imbalanced metabolism of the kynurenine pathway in the PFC of FSL rats.

scholarly journals Localization of Indoleamine 2,3-Dioxygenase-1 and Indoleamine 2,3-Dioxygenase-2 at the Human Maternal-Fetal Interface

2020 ◽  
Vol 13 ◽  
pp. 117864692098416
Author(s):  
Yoshiki Kudo ◽  
Iemasa Koh ◽  
Jun Sugimoto
Keyword(s):  
Interferon Γ ◽  
Kynurenine Pathway ◽  
Explant Culture ◽  
Immunohistochemical Localization ◽  
Tryptophan Metabolism ◽  
Indoleamine 2,3 Dioxygenase ◽  
Cellular Expression ◽  
Normal Human ◽  
Protein Immunoreactivity ◽  
Maternal Fetal Interface

Immunohistochemical localization of indoleamine 2,3-dioxygenase-1 and indoleamine 2,3-dioxygenase-2, the first and rate-limiting enzyme in tryptophan metabolism along the kynurenine pathway, has been studied in order to better understand the physiological significance of these enzymes at the maternal-fetal interface of human pregnancy with a gestational age of 7 weeks (n = 1) and term placentas (37-40 weeks of gestation, n = 5). Indoleamine 2,3-dioxygenase-1 protein immunoreactivity was found in glandular epithelium of the decidua and the endothelium of the fetal blood vessels in the villous stroma with some additional positive cells in the villous core and in the decidua. The syncytiotrophoblast stained strongly for indoleamine 2,3-dioxygenase-2. Immunoreactivity of kynurenine, the immediate downstream product of indoleamine 2,3-dioxygenase-mediated tryptophan metabolism, showed the same localization as that of indoleamine 2,3-dioxygenase-1 and indoleamine 2,3-dioxygenase-2, suggesting these are functional enzymes. Interferon-γ added to placental villous explant culture markedly stimulated expression level of both mRNA and immunoreactivity of indoleamine 2,3-dioxygenase-1. The different cellular expression and interferon-γ sensitivity of these enzymes at the maternal-fetal interface suggests distinct physiological roles for each enzyme in normal human viviparity.

scholarly journals Iron activates microglia and directly stimulates indoleamine-2,3-dioxygenase activity in the N171-82Q mouse model of Huntington’s disease

2019 ◽  
Author(s):  
David W. Donley ◽  
Marley Realing ◽  
Jason P. Gigley ◽  
Jonathan H. Fox
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Microglial Activation ◽  
Iron Supplementation ◽  
Kynurenine Pathway ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tryptophan Degradation ◽  
Microglial Morphology

AbstractHuntington’s disease (HD) is a neurodegenerative disorder caused by a dominant CAG-repeat expansion in the huntingtin gene. Morphologic activation of microglia is a key marker of neuroinflammation that is present before clinical onset in HD patients. The kynurenine pathway of tryptophan degradation is restricted in part to microglia and is activated in HD, where it contributes to disease progression. Indoleamine-2,3-dioxygenase (IDO) is a microglial enzyme that catalyzes the first step in this pathway. HD brain microglial cells also accumulate iron; however, the role of iron in promoting microglial activation and the kynurenine pathway is unclear. Based on analyses of morphological characteristics of microglia, we showed that HD mice demonstrate an activated microglial morphology compared with controls. Neonatal iron supplementation resulted in additional microglial morphology changes compared with HD controls. Increased microglial activation in iron-supplemented HD mice was indicated by increased soma volume and decreased process length. In our assessment of whether iron can affect the kynurenine pathway, iron directly enhanced the activity of human recombinant IDO1 with an EC50 of 1.24 nM. We also detected elevated microglial cytoplasmic labile iron in N171-82Q HD mice, an increase that is consistent with the cellular location of IDO. We further demonstrated that neonatal iron supplementation, a model for studying the role of iron in neurodegeneration, activates IDO directly in the mouse brain and promotes neurodegeneration in HD mice. Kynurenine pathway metabolites were also modified in HD and by iron supplementation in wild-type mice. These findings indicate that iron dysregulation contributes to the activation of microglia and the kynurenine pathway in a mouse model of HD.

The immunometabolic role of indoleamine 2,3-dioxygenase in atherosclerotic cardiovascular disease: immune homeostatic mechanisms in the artery wall

2019 ◽  
Vol 115 (9) ◽  
pp. 1408-1415 ◽  
Author(s):  
Daniel F J Ketelhuth
Keyword(s):  
Current Knowledge ◽  
Large Body ◽  
Vascular Wall ◽  
Kynurenine Pathway ◽  
Atherosclerotic Cardiovascular Disease ◽  
Artery Wall ◽  
Indoleamine 2,3 Dioxygenase ◽  
Rate Limiting ◽  
Accumulation Of Lipids

AbstractCoronary heart disease and stroke, the two most common cardiovascular diseases worldwide, are triggered by complications of atherosclerosis. Atherosclerotic plaques are initiated by a maladaptive immune response triggered by accumulation of lipids in the artery wall. Hence, disease is influenced by several non-modifiable and modifiable risk factors, including dyslipidaemia, hypertension, smoking, and diabetes. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the kynurenine pathway of tryptophan (Trp) degradation, is modulated by inflammation and regarded as a key molecule driving immunotolerance and immunosuppressive mechanisms. A large body of evidence indicates that IDO-mediated Trp metabolism is involved directly or indirectly in atherogenesis. This review summarizes evidence from basic and clinical research showing that IDO is a major regulatory enzyme involved in the maintenance of immunohomeostasis in the vascular wall, as well as current knowledge about promising targets for the development of new anti-atherosclerotic drugs.

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