IDO expression in the brain: a double-edged sword

Kwidzinski, Erik; Bechmann, Ingo

doi:10.1007/s00109-007-0229-7

Cited by 135 publications

(108 citation statements)

References 86 publications

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“…In support of this, we previously showed increased IFN␥ and IL-1␤ mRNA in the diabetic HYPO (30). In the brain, enhanced IDO expression increases production of neurotoxins such as QUIN and 3-hydroxyanthranic acid to lead to neurodegeneration (41).…”

Section: /Cd39mentioning

confidence: 62%

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Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice

Thinschmidt

Caballero

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Hu P, Thinschmidt JS, Caballero S, Adamson S, Cole L, Chan-Ling T, Grant MB. Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice. Am J Physiol Endocrinol Metab 308: E688 -E698, 2015. First published February 24, 2015 doi:10.1152/ajpendo.00504.2014.-Neuroinflammation and neurodegeneration have been observed in the brain in type 1 diabetes (T1D). However, little is known about the mediators of these effects. In T1D mice with 12-and 35-wk duration of diabetes we examined two mechanisms of neurodegeneration, loss of the neuroprotective factors insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) and changes in indoleamine 2,3-dioxygenase (IDO) expression in the brain, and compared the response to age-matched controls. Furthermore, levels of matrix metalloproteinase-2 (MMP-2), nucleoside triphosphate diphosphohydrolase-1 (CD39), and ionized calcium-binding adaptor molecule 1 (Iba-1) were utilized to assess inflammatory changes in astrocytes, microglia, and blood vessels. In the diabetic hypothalamus (HYPO), we observed 20% reduction in neuronal soma diameter (P Ͻ 0.05) and reduced neuronal expression of IGFBP-3 (Ϫ32%, P Ͻ 0.05) and IGF-I (Ϫ15%, P Ͻ 0.05) compared with controls at 35 wk. In diabetic HYPO, MMP-2 expression was increased in astrocytes (46%, P Ͻ 0.01), and IDO ϩ cell density rose by (62%, P Ͻ 0.05). CD39 expression dropped by 30% (P Ͻ 0.05) in microglia and blood vessels. With 10 wk of systemic treatment using minocycline, an anti-inflammatory agent that crosses the blood-brain barrier, MMP-2, IDO, and CD39 levels normalized (P Ͻ 0.05). Our results suggest that increased IDO and early loss of CD39 ϩ protective cells lead to activation of inflammation in sympathetic centers of the CNS. As a downstream effect, the loss of the neuronal survival factors IGFBP-3 and IGF-I and the neurotoxic products of the kynurenine pathway contribute to the loss of neuronal density observed in the HYPO in T1D.

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Section: /Cd39mentioning

confidence: 62%

“…IDO expression is low in normal CNS but increases greatly during inflammatory conditions (1). Proinflammatory cytokines and molecules, especially interferon-␥, increase IDO expression (41). With the increases in IDO expression, the KP downstream products, e.g., quinolinic acid (QUIN), typically rise and have direct effects on neuronal toxicity.…”

mentioning

confidence: 99%

Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice

Thinschmidt

Caballero

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…Structurally similar to IDO-1, IDO-2 is encoded by a gene downstream of the IDO-1 gene (14). TDO-2, which is primarily expressed within the liver (17)(18)(19), but also expressed in a variety of other tissues including the brain (18,(20)(21)(22)(23), catabolises the majority of dietary tryptophan for the maintenance of basal serum levels (24) and is induced by the availability of dietary tryptophan as well as tyrosine, histidine, glucocorticoids, and kynurenine (25,26).…”

Section: The Kynurenine Pathwaymentioning

confidence: 99%

The Kynurenine Pathway in Brain Tumor Pathogenesis

et al. 2012

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Brain tumors are among the most common and most chemoresistant tumors. Despite treatment with aggressive treatment strategies, the prognosis for patients harboring malignant gliomas remains dismal. The kynurenine pathway (KP) is the principal route of L-tryptophan catabolism leading to the formation of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD þ ), and important neuroactive metabolites, including the neurotoxin, quinolinic acid (QUIN), the neuroprotective agent, picolinic acid (PIC), the T H 17/Treg balance modulator, 3-hydroxyanthranilic acid (3-HAA), and the immunosuppressive agent, L-Kynurenine (KYN). This review provides a new perspective on KP dysregulation in defeating antitumor immune responses, specifically bringing light to the lower segment of the KP, particularly QUIN-induced neurotoxicity and downregulation of the enzyme a-amino-b-carboxymuconate-e-semialdehyde decarboxylase (ACMSD) as a potential mechanism of tumor progression. Given its immunosuppressive effects, 3-HAA produced from the KP may also play a role in suppressing antitumor immunity in human tumors. The enzyme indoleamine 2, 3-dioxygenase (IDO-1) initiates and regulates the first step of the KP in most cells. Mounting evidence directly implicates that the induction and overexpression of IDO-1 in various tumors is a crucial mechanism facilitating tumor immune evasion and persistence. Tryptophan 2, 3-dioxygenase (TDO-2), which initiates the same first step of the KP as IDO-1, has likewise recently been shown to be a mechanism of tumoral immune resistance. Further, it was also recently shown that TDO-2-dependent production of KYN by brain tumors might be a novel mechanism for suppressing antitumor immunity and supporting tumor growth through the activation of the Aryl hydrocarbon receptor (AhR). This newly identified TDO-2-KYN-AhR signaling pathway opens up exciting future research opportunities and may represent a novel therapeutic target in cancer therapy. Our discussion points to a number of KP components, namely TDO-2, IDO-1, and ACMSD, as important therapeutic targets for the treatment of brain cancer. Targeting the KP in brain tumors may represent a viable strategy likely to prevent QUIN-induced neurotoxicity and KYN and 3-HAA-mediated immune suppression. Cancer Res; 72(22); 5649-57. Ó2012 AACR.

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“…IDO and TDO metabolize tryptophan into kynurenine, which can be further metabolized into biologically active metabolites. Kynurenine aminotransferases can metabolize kynurenine into the neuroprotective NMDA antagonist kyunurenic acid, which occurs primarily in astrocytes, brain endothelial cells, and neurons (Guillemin et al, 2005;Kwidzinski and Bechmann, 2007). In microglia and macrophages, however, there is a bias for metabolized kynurenine to be shunted down the pathways, which results in the formation of the neurotoxic NMDA receptor agonist quinolinic acid (Heyes et al, 1996;Guillemin et al, 2005).…”

Section: Grk2mentioning

confidence: 99%