Cited by 497Tryptophan and brain disordersNeuroinflammation and Neurodegeneration MechanismsAmino Acid Enzymes and Metabolism

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Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons

Guillemin, Gilles J., Smythe, George, Takikawa, Osamu, Brew, Bruce J.·2005·Glia

DOI 10.1002/glia.20090

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Abstract

There is good evidence that the kynurenine pathway (KP) and one of its end products, quinolinic acid (QUIN) play a role in the pathogenesis of several major neurological diseases. While QUIN has been shown to be produced in neurotoxic concentrations by macrophages and microglia, the capacity of astrocytes and neurons to produce QUIN is controversial. Using interferon gamma (IFN‐γ)‐stimulated primary cultures of human mixed brain cells, we assayed expression of the KP regulatory enzyme indoleamine 2,3‐dioxygenase (IDO) and QUIN production by immunocytochemistry. Using IFN‐γ‐stimulated purified cultures of neurons, astrocytes, microglia and macrophages, we studied IDO expression by RT‐PCR and production of QUIN using mass spectrometry. We found that astrocytes, neurons, and microglia expressed IDO but only microglia were able to produce detectable amounts of QUIN. However, astrocytes and neurons had the ability to catabolize QUIN. This study also provides the first evidence of IDO expression and lack of production of QUIN in culture of primary human neurons. © 2004 Wiley‐Liss, Inc.

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Recent advances in psychoneuroimmunology: Inflammation in psychiatric disorders
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Immunomodulatory Effects of Tryptophan Metabolism in the Glioma Tumor Microenvironment
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High neopterin and IP-10 levels in cerebrospinal fluid are associated with neurotoxic tryptophan metabolites in acute central nervous system infections
Quist‐Paulsen, E., Aukrust, P., Kran, A. B., Dunlop, O., Ormaasen, V., Stiksrud, B., Midttun, Ø., Ueland, T., Ueland, P. M., Mollnes, T. E., et al. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1366-3 · Cited by 31
Quinolinic acid/tryptophan ratios predict neurological disease in SIV-infected macaques and remain elevated in the brain under cART
Drewes, J. L., Meulendyke, K. A., Liao, Z., Witwer, K. W., Gama, L., Ubaida‐Mohien, C., Li, M., Notarangelo, F. M., Tarwater, P. M., Schwarcz, R. M., et al. (2015) · Journal of NeuroVirology · doi:10.1007/s13365-015-0334-2 · Cited by 43
“Determining the cellular localization of KP enzymes within the brain remains an important future direction, although previous studies have consistently highlighted macrophages and microglia as the most important cerebral sources of IDO expression and quinolinic acid production in humans and in rhesus macaques, while h…”
Vascular expression, activity and function of indoleamine 2,3-dioxygenase-1 following cerebral ischaemia–reperfusion in mice
Jackman, K. A., Brait, V. H., Wang, Y.-T., Maghzal, G. J., Ball, H., McKenzie, G., Silva, T. D. D., Stocker, R., & Sobey, C. (2011) · Naunyn-Schmiedeberg's Archives of Pharmacology · doi:10.1007/s00210-011-0611-4 · Cited by 28
“In the human brain, Ido is expressed in response to stimulation with IFNγ in the cortex and hippocampus (Guillemin et al. 2007), and it has been shown to be localized in neurons, astrocytes, microglia, macrophages and microvascular endothelial cells ( Guillemin et al. 2001, 2005, 2007 ).”
Background
Sphingosine kinase 2 potentiates amyloid deposition but protects against hippocampal volume loss and demyelination in a mouse model of Alzheimer’s disease
Lei, M., Teo, J. D., Song, H., McEwen, H. P., Yup Lee, J., Couttas, T. A., Duncan, T., Chesworth, R., Bertz, J., Przybyla, M., et al. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.0524-19.2019 · Cited by 27
“Primary human embryonic astrocytes were isolated from the Human Fetal Tissue Biobank at Macquarie University Hospital, under ethics approval #5201600719 (Guillemin et al., 2005), and cultured in RPMI medium with 10% FBS and 2 mM L-glutamine.”
MethodSelf-citation
The interplay between metabolism and neuroinflammation in epilepsy: mechanisms and therapeutic perspectives
Xu, L., Zhao, Z., Zhang, Y., & Ma, C.-L. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03553-w · Cited by 27
Direct and indirect effects of microbiota-derived metabolites on neuroinflammation in multiple sclerosis
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Tryptophan metabolism in health and disease- implications for non-communicable diseases
Gabela, A. M., Mthembu, N., & Hadebe, S. (2025) · Immunology Letters · doi:10.1016/j.imlet.2025.107093 · Cited by 31
Latest developments in tryptophan metabolism: Understanding its role in B cell immunity
Dagenais-Lussier, X., Loucif, H., Beji, C., Telittchenko, R., Routy, J., & van Grevenynghe, J. (2021) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2021.02.003 · Cited by 43
Roflumilast, a cAMP-Specific Phosphodiesterase-4 Inhibitor, Reduces Oxidative Stress and Improves Synapse Functions in Human Cortical Neurons Exposed to the Excitotoxin Quinolinic Acid
Bhat, A., Tan, V. X., Heng, B., Lovejoy, D. B., Sakharkar, M. K., Essa, M. M., Chidambaram, S. B., & Guillemin, G. J. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00636 · Cited by 27
Self-citation
Cyclooxygenase Inhibition Safety and Efficacy in Inflammation-Based Psychiatric Disorders
Perrone, M. G., Centonze, A., Miciaccia, M., Ferorelli, S., & Scilimati, A. (2020) · Molecules · doi:10.3390/molecules25225388 · Cited by 31
“On the contrary, as a consequence of the activation of the microglia from stress or inflammation, the neurodegenerative pathway predominates [82], with a consequent increase of levels of quinolinic acid and 3-hydroxy-kynurenine, two excitotoxic metabolites acting as agonists of the NMDA receptor [47,83,84] and inducin…”
Background
Prospective study of the effects of sport-related concussion on serum kynurenine pathway metabolites
Meier, T. B., Nitta, M. E., Teague, T. K., Nelson, L. D., McCrea, M., & Savitz, J. B. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.03.002 · Cited by 37
“QuinA is thought to be made by microglia in the brain and macrophages in the periphery (Espey et al., 1997; Guillemin et al., 2005), and thus the elevation in circulating concentrations of QuinA in the SRC group with a concussion history is consistent with the possibility that prior concussions result in the long-term…”
Result
Physical exercise prevents mice from L-Kynurenine-induced depression-like behavior.
Su, C., Chuang, H., & Hong, C. (2019) · Asian Journal of Psychiatry · doi:10.1016/j.ajp.2019.101894 · Cited by 26
Increased quinolinic acid in peripheral mononuclear cells in Alzheimer’s dementia
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Biochemical, histopathological and behavioral alterations caused by intrastriatal administration of quinolic acid to young rats
Pierozan, P., Fernandes, C. G., Dutra, M. F., Pandolfo, P., Ferreira, F. S., de Lima, B. O., Porciúncula, L. O., Wajner, M., & Pessoa‐Pureur, R. (2014) · FEBS Journal · doi:10.1111/febs.12762 · Cited by 27
Inhibition of indoleamine 2,3-dioxygenase prevented cognitive impairment in adult Wistar rats subjected to pneumococcal meningitis
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Recent Advances in Current Uptake Situation, Metabolic and Nutritional Characteristics, Health, and Safety of Dietary Tryptophan
Zhu, H., Yang, X., & Zhao, Y. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.3c06419 · Cited by 28
Toxoplasmosis: Targeting neurotransmitter systems in psychiatric disorders
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Hoffman, W., Whelan, S., & Lee, N. (2021) · PLoS ONE · doi:10.1371/journal.pone.0254116 · Cited by 25
The neurobiology of HIV dementia: implications for practice in South Africa.
Joska, J., Hoare, J., Stein, D. J., & Flisher, A. (2011) · The African journal of psychiatry · doi:10.4314/ajpsy.v14i1.65463 · Cited by 25
Effect of indoleamine dioxygenase-1 deficiency and kynurenine pathway inhibition on murine cerebral malaria.
Miu, J., Ball, H., Mellor, A., & Hunt, N. (2009) · International Journal of Parasitology · doi:10.1016/j.ijpara.2008.10.005 · Cited by 25
Neuronal localization of indoleamine 2,3-dioxygenase in mice
Roy, E. J., Takikawa, O., Kranz, D. M., Brown, A. R., & Thomas, D. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2005.07.010 · Cited by 29
Self-citation
Sustained elevation of kynurenic Acid in the cerebrospinal fluid of patients with herpes simplex virus type 1 encephalitis
Atlas, A., Franzen-Röhl, E., Söderlund, J., Jönsson, E. G., Samuelsson, M., Schwieler, L., Sköldenberg, B., & Engberg, G. (2013) · International Journal of Tryptophan Research · doi:10.4137/ijtr.s13256 · Cited by 25
Neuroimmune modulation by tryptophan derivatives in neurological and inflammatory disorders
Kondo, T., Okada, Y., Saika, S., Yamaguchi, N., Hatakeyama, S., & Maruyama, K. (2024) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2024.151418 · Cited by 24
Neurotoxic potential of reactive astrocytes in canine distemper demyelinating leukoencephalitis
Klemens, J., Ciurkiewicz, M., Chludzinski, E., Iseringhausen, M., Klotz, D., Pfankuche, V., Ulrich, R., Herder, V., Puff, C., Baumgärtner, W., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-48146-9 · Cited by 24
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Cerebral dopamine neurotrophic factor (CDNF) protects against quinolinic acid-induced toxicity in in vitro and in vivo models of Huntington’s disease
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PCC0208009, an indirect IDO1 inhibitor, alleviates neuropathic pain and co-morbidities by regulating synaptic plasticity of ACC and amygdala
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Individualized Immunological Data for Precise Classification of OCD Patients
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A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease
Summers, B. S., Broome, S. T., Pang, T. W. R., Mundell, H. D., Belic, N. K., Tom, N., Ng, M. L., Yap, M. L., Sen, M. K., Sedaghat, S., et al. (2024) · International Journal of Tryptophan Research · doi:10.1177/11786469241248287 · Cited by 28
“159 This may be at least partially driven by KP agonism of AhR, which is expressed by HSCs, 168 as the AhR agonist 2,3,7,8-tetrachlo-rodibenzo-p-dioxin (TCDD) inhibits the proliferation of HSCs and immature hematopoietic progenitor cells.”
BackgroundSelf-citation
Understanding the balance and integration of volume and synaptic transmission. Relevance for psychiatry
Fuxé, K., Borroto‐Escuela, D. O., Tarakanov, A. O., Romero‐Fernandez, W., Manger, P. R., Rivera, A., Craenenbroeck, K. V., Skieterska, K., Díaz-Cabiale, Z., Filip, M., et al. (2013) · Neurology Psychiatry and Brain Research · doi:10.1016/j.npbr.2013.10.002 · Cited by 26
Depression has a Strong Relationship to Alterations in the Immune, Endocrine and Neural System
Hestad, K. A., Aukrust, P., Tønseth, S., & Reitan, S. K. (2009) · Current Psychiatry Reviews · doi:10.2174/157340009789542105 · Cited by 20
“Kynurenin metabolites 3-hydroxy-kynurenine (3OH-KYN) and quinoline acid (QUIN) are produced in astrocytes and glial cells [141, 142].”
Background
Inflammation Effects on Glutamate as a Pathway to Neuroprogression in Mood Disorders
Haroon, E., & Miller, A. H. (2017) · Modern trends in psychiatry · doi:10.1159/000470805 · Cited by 22
Xanthurenic acid is localized in neurons in the central nervous system
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“QUIN is produced by activated monocytic cells (Guillemin et al. 2005), while KYNA is synthesised by astrocytes (Guillemin et al. 2001).”
BackgroundSelf-citation
Soluble LILRA3 promotes neurite outgrowth and synapses formation through a high-affinity interaction with Nogo 66
An, H., Brettle, M., Lee, T., Heng, B., Lim, C. K., Guillemin, G. J., Lord, M. S., Klotzsch, E., Geczy, C. L., Bryant, K., et al. (2016) · Journal of Cell Science · doi:10.1242/jcs.182006 · Cited by 23
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Modulation of indoleamine‐2,3‐dioxygenase expression and activity by HIV‐1 in human macrophages
Manéglier, B., Malleret, B., Guillemin, G. J., Spreux‐Varoquaux, O., Devillier, P., Rogez‐Kreuz, C., Porcheray, F., Thérond, P., Dormont, D., & Clayette, P. (2009) · Fundamental & Clinical Pharmacology · doi:10.1111/j.1472-8206.2009.00703.x · Cited by 21
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The L-kynurenine signalling pathway in trigeminal pain processing: A potential therapeutic target in migraine?
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Hypoxia and the Kynurenine Pathway: Implications and Therapeutic Prospects in Alzheimer’s Disease
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“Several morphological and pathological studies suggest that NDs may arise due to mitochondrial dysfunction, genetic predisposition, and environmental factors [2, 3].”
Background
Positive association between serum quinolinic acid and functional connectivity following concussion
Meier, T. B., España, L. Y., Nitta, M. E., Teague, T. K., Brett, B. L., Nelson, L. D., McCrea, M., & Savitz, J. B. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.11.011 · Cited by 29
Human Neural Stem Cell Systems to Explore Pathogen-Related Neurodevelopmental and Neurodegenerative Disorders
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Effect of selective serotonin reuptake inhibitor on prefrontal-striatal connectivity is dependent on the level of TNF-α in patients with major depressive disorder
Liu, K., Zhao, X., Lu, X., Zhu, X., Chen, H., Wang, M., Yan, W., Jing, L., Deng, Y., Yu, L., et al. (2018) · Psychological Medicine · doi:10.1017/s0033291718003616 · Cited by 18
“On the other hand, the accumulated production of quinolinic acid by the KYN pathway may result in excitotoxicity to neurons (Guillemin et al., 2005).”
Background

Authors: Guillemin, G. J., Smythe, G., Takikawa, O., & Brew, B. J.
Affiliations: UNSW Sydney (AU)
Hokkaido University (JP)
Corresponding author: Guillemin, Gilles J.
ORCID: Guillemin, Gilles J.
Brew, Bruce J.
Venue: Glia
Publisher: Wiley
Published: 2004-07-06
Volume: 49
Issue: 1
Pages: 15-23
ISSN: 0894-1491 (ISSN-L)
1098-1136
DOI: 10.1002/glia.20090
OpenAlex: W2042731928
Cited by: 497
References: 0
Citations by year: 2026: 17 · 2025: 15 · 2024: 27 · 2023: 15 · 2022: 30 · 2021: 29 · 2020: 40 · 2019: 23 · 2018: 26 · 2017: 25 · 2016: 36 · 2015: 19 · 2014: 30 · 2013: 30 · 2012: 19
FWCI: 5.62
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Glia (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords: indoleamine 2,3-dioxygenase, quinolinic acid, kynurenine pathway, microglia, astrocytes, neurons, interferon-gamma, neuroinflammation
MeSH terms: Astrocytes, Brain, Brain Chemistry, Cells, Cultured, Encephalitis, Humans, Immunohistochemistry, Interferon-gamma, Kynurenine, Macrophages, Neurons, Mass Spectrometry, Tryptophan Oxygenase, Molecular Structure, Signal Transduction, Quinolinic Acid, Microglia, Coculture Techniques, Indoleamine-Pyrrole 2,3,-Dioxygenase

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Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons

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