Synthesis and release of neurotoxic kynurenine metabolites by human monocyte-derived macrophages

Chiarugi, Alberto; Calvani, Maura; Meli, Elena; Traggiai, Elisabetta; Moroni, Flavio

doi:10.1016/s0165-5728(01)00418-0

Cited by 113 publications

(86 citation statements)

References 34 publications

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“…Still, this switch relies on the presence of infiltrating microglial cells as a provider of quinolinic acid. Studies in monocytic cells including microglial cells have indicated their capability of accumulating quinolinic acid after induction of IDO-1 by inflammatory mediators (12,53,54). Our results indicate that glioma cells themselves are not capable of metabolizing tryptophan to quinolinic acid as they lack the key enzyme 3-HAO (Fig.…”

Section: Discussionmentioning

confidence: 69%

The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress

et al. 2013

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Quinolinic acid is a product of tryptophan degradation and may serve as a precursor for NAD þ , an important enzymatic cofactor for enzymes such as the DNA repair protein PARP. Pathologic accumulation of quinolinic acid has been found in neurodegenerative disorders including Alzheimer and Huntington disease, where it is thought to be toxic for neurons by activating the N-methyl-D-aspartate (NMDA) receptor and inducing excitotoxicity. Although many tumors including gliomas constitutively catabolize tryptophan, it is unclear whether quinolinic acid is produced in gliomas and whether it is involved in tumor progression. Here, we show that quinolinic acid accumulated in human gliomas and was associated with a malignant phenotype. Quinolinic acid was produced by microglial cells, as expression of the quinolinic acid-producing enzyme 3-hydroxyanthranilate oxygenase (3-HAO) was confined to microglia in glioma tissue. Human malignant glioma cells, but not nonneoplastic astrocytes, expressed quinolinic acid phosphoribosyltransferase (QPRT) to use quinolinic acid for NAD þ synthesis and prevent apoptosis when de novo NAD þ synthesis was blocked.Oxidative stress, temozolomide, and irradiation induced QPRT in glioma cells. QPRT expression increased with malignancy. In recurrent glioblastomas after radiochemotherapy, QPRT expression was associated with a poor prognosis in two independent datasets. Our data indicate that neoplastic transformation in astrocytes is associated with a QPRT-mediated switch in NAD þ metabolism by exploiting microglia-derived quinolinic acid as an alternative source of replenishing intracellular NAD þ pools. The elevated levels of QPRT expression increase resistance to oxidative stress induced by radiochemotherapy, conferring a poorer prognosis. These findings have implications for therapeutic approaches inducing intracellular NAD þ depletion, such as alkylating agents or direct NAD þ synthesis inhibitors, and identify QPRT as a potential therapeutic target in malignant gliomas. Cancer Res; 73(11); 3225-34. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 69%

The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress

et al. 2013

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“…In this study, we have provided evidence that 1) IDO is the major relevant target of pharmacologic inhibition of the kynurenine pathway when racemic 1-MT is used as an enzyme inhibitor; 2) DCs express the entire metabolic machinery necessary for synthesis of QUIN; 3) IFN-␥ enhances the transcriptional expression of all these enzymes, which may in fact respond as a coordinately regulated cluster of genes (45); yet, posttranslational inactivation of IDO occurs in nontolerogenic CD8 Ϫ DCs, and this prevents the action of enzymes consequent to IDO function; and 4) bypassing the IDOassociated blockade by the addition of a downstream QUIN precursor initiates the pathway and leads to the onset of suppressive properties in CD8 Ϫ DCs treated with IFN-␥. Human macrophages are endowed with the ability to convert tryptophan to QUIN (46,47); yet, no information was previously available regarding the functional expression of kynurenine pathway enzymes other than IDO in human or murine DCs. We found that the splenic CD8 ϩ subset of murine DCs could be induced by IFN-␥ to release high levels of QUIN.…”

Section: Discussionmentioning

confidence: 99%

Kynurenine Pathway Enzymes in Dendritic Cells Initiate Tolerogenesis in the Absence of Functional IDO

Belladonna

Grohmann

Guidetti

et al. 2006

The Journal of Immunology

161

120

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Dendritic cell (DC) tryptophan catabolism has emerged in recent years as a major mechanism of peripheral tolerance. However, there are features of this mechanism, initiated by IDO, that are still unclear, including the role of enzymes that are downstream of IDO in the kynurenine pathway and the role of the associated production of kynurenines. In this study, we provide evidence that 1) murine DCs express all enzymes necessary for synthesis of the downstream product of tryptophan breakdown, quinolinate; 2) IFN-γ enhances transcriptional expression of all of these enzymes, although posttranslational inactivation of IDO may prevent metabolic steps that are subsequent and consequent to IDO; 3) overcoming the IDO-dependent blockade by provision of a downstream quinolinate precursor activates the pathway and leads to the onset of suppressive properties; and 4) tolerogenic DCs can confer suppressive ability on otherwise immunogenic DCs across a Transwell in an IDO-dependent fashion. Altogether, these data indicate that kynurenine pathway enzymes downstream of IDO can initiate tolerogenesis by DCs independently of tryptophan deprivation. The paracrine production of kynurenines might be one mechanism used by IDO-competent cells to convert DCs lacking functional IDO to a tolerogenic phenotype within an IFN-γ-rich environment.

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“…Sequential activation by the enzymes kynurenine monooxygenase (KMO) and kynureninase results in the formation of the neurotoxic molecules 3-hydroxy kynurenine (3HK), anthranilic acid (AA), 3-hydroxy anthranilic acid (HANA), and QUIN that are ultimately converted to nicotinic acid adenine dinucleotide (NAD). 3HK, AA and, HANA all are known to trigger profound oxidative stress and precipitate cell death (Chiarugi et al, 2001a;Chiarugi et al, 2001b;Guidetti and Schwarcz, 1999). They also indirectly contribute to glutamate increases by increasing the need for GSH and activating the xC-system.…”

Section: Kyn Pathway and Its Downstream Metabolitesmentioning

confidence: 99%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

414

299

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Increasing data indicate that inflammation and alterations in glutamate neurotransmission are two novel pathways to pathophysiology in mood disorders. The primary goal of this review is to illustrate how these two pathways may converge at the level of the glia to contribute to neuropsychiatric disease. We propose that a combination of failed clearance and exaggerated release of glutamate by glial cells during immune activation leads to glutamate increases and promotes aberrant extrasynaptic signaling through ionotropic and metabotropic glutamate receptors, ultimately resulting in synaptic dysfunction and loss. Furthermore, glutamate diffusion outside the synapse can lead to the loss of synaptic fidelity and specificity of neurotransmission, contributing to circuit dysfunction and behavioral pathology. This review examines the fundamental role of glia in the regulation of glutamate, followed by a description of the impact of inflammation on glial glutamate regulation at the cellular, molecular, and metabolic level. In addition, the role of these effects of inflammation on glia and glutamate in mood disorders will be discussed along with their translational implications.

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Synthesis and release of neurotoxic kynurenine metabolites by human monocyte-derived macrophages

Cited by 113 publications

References 34 publications

The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress

The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress

Kynurenine Pathway Enzymes in Dendritic Cells Initiate Tolerogenesis in the Absence of Functional IDO

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

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