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Investigation of the kynurenine pathway in Indoleamine 2, 3 dioxygenase deficient mice with inflammatory arthritis.

ABSTRACT: Tryptophan is an essential amino acid involved in the protein synthesis, cognition, and immunity. Oxidative catabolism of tryptophan is executed by the sets of biochemical reactions collectively referred to as the kynurenine pathway. In the immune system, two distinct enzymes, Indoleamne 2,3 dioxygenase 1 (IDO1) and Indoleamine 2, 3 dioxygenase 2 (IDO2) can initiate metabolic flux through the kynurenine pathway. Rheumatoid arthritis is an autoimmune disease driven by the exacerbated immune response towards self antigens and characterized by the chronic inflammatory reaction of the diarthrodial joints. Collagen induced arthritis (CIA) is an animal model of rheumatoid arthritis. Using CIA in wild type (WT) and mice deficient with Indoleamine 2,3 dioxygenase (Ido1KO), it was of interest to test the impact of Ido1 deletion on the concentration of tryptophan and its catabolites as well as on mRNA expression for other genes on the kynurenine pathway. Here, when compared with samples taken from naïve WT animals and those with CIA, it was found that only in the inguinal lymph nodes (iLN) taken from Ido1KO mice with CIA tryptophan concentration was significantly increased. In contrast, mRNA expression for Ido2 was decreased in naïve as well as in the diseased iLN taken from Ido1KO mice. Deletion of Ido1 and reduced mRNA expression for Ido2 neither affected the concentration of the downstream metabolites of tryptophan nor mRNA expression for downstream genes on the kynurenine pathway in iLN. Moreover, the concentration of kynurenine in sera of mice with CIA was significantly decreased in Ido1KO mice with arthritis.

SUBMITTER: Kolodziej L

PROVIDER: S-EPMC3781305 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Investigation of the kynurenine pathway in Indoleamine 2, 3 dioxygenase deficient mice with inflammatory arthritis.

Kolodziej Lukasz L

Transgenic research 20130217 5

Tryptophan is an essential amino acid involved in the protein synthesis, cognition, and immunity. Oxidative catabolism of tryptophan is executed by the sets of biochemical reactions collectively referred to as the kynurenine pathway. In the immune system, two distinct enzymes, Indoleamne 2,3 dioxygenase 1 (IDO1) and Indoleamine 2, 3 dioxygenase 2 (IDO2) can initiate metabolic flux through the kynurenine pathway. Rheumatoid arthritis is an autoimmune disease driven by the exacerbated immune respo ...[more]

PMID: 23417792

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Project description:Aim:Poststroke depression (PSD), which occurs in approximately one-third of stroke survivors, is clinically important because of its association with slow functional recovery and increased mortality. In addition, the underlying pathophysiological mechanisms are still poorly understood. Methods:We used a mouse model of PSD to examine the neurobiological mechanisms of PSD and the beneficial effects of aripiprazole, an atypical antipsychotic drug. PSD was induced in mice by combining middle cerebral artery occlusion (MCAO) with spatial restraint stress. The body weight, sucrose preference, and forced swim tests were performed at 5, 7, and 9 weeks and the Morris water maze test at 10 weeks after completing MCAO and spatial restraint stress. Results:Mice subjected to MCAO and spatial restraint stress showed significant depressive-like behavior in the sucrose preference test and forced swim test as well as cognitive impairment in the Morris water maze test. The PSD-like phenotype was accompanied by an indoleamine 2,3-dioxygenase 1 (IDO1) expression increase in the nucleus accumbens, hippocampus, and hypothalamus, but not in the striatum. Furthermore, the increased IDO1 levels were localized in Iba-1(+) cells but not in NeuN(+) or GFAP(+) cells, indicating that microglia-induced IDO1 expression was prominent in the PSD mouse brain. Moreover, 3-hydroxyanthranilate 3,4-dioxygenase (HAAO), quinolinic acid (QUIN), and reactive oxygen species (ROS) were significantly increased in the nucleus accumbens, hippocampus, and hypothalamus of PSD mice. Importantly, a 2-week aripiprazole (1 mg/kg, per os) regimen, which was initiated 1 day after MCAO, ameliorated depressive-like behavior and impairment of cognitive functions in PSD mice that was accompanied by downregulation of IDO1, HAAO, QUIN, and ROS. Conclusions:Our results suggest that the IDO1-dependent neurotoxic kynurenine metabolism induced by microglia functions in PSD pathogenesis. The beneficial effect of aripiprazole on depressive-like behavior and cognitive impairment may be mediated by inhibition of IDO1, HAAO, QUIN, and ROS.

Dataset Information

Investigation of the kynurenine pathway in Indoleamine 2, 3 dioxygenase deficient mice with inflammatory arthritis.

Publications

Investigation of the kynurenine pathway in Indoleamine 2, 3 dioxygenase deficient mice with inflammatory arthritis.

Similar Datasets

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