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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IDO and Kynurenine Metabolites in Peripheral and CNS Disorders
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Kynurenine Pathway Enzymes in Dendritic Cells Initiate Tolerogenesis in the Absence of Functional IDO
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“Astrocytes, neurons, and microglia all express IDO, but only microglial cells are capable of producing substantial quantities of QUIN (39).”
Background
Characterisation of the Expression of NMDA Receptors in Human Astrocytes
Lee, M.-C., Ting, K. K., Adams, S., Brew, B. J., Chung, R. S., & Guillemin, G. J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0014123 · Cited by 195
“The method is previously described [30,31].”
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The Physiological Action of Picolinic Acid in the Human Brain
Grant, R., Coggan, S. E., & Smythe, G. A. (2009) · International Journal of Tryptophan Research · doi:10.4137/ijtr.s2469 · Cited by 219
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The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases
Hestad, K. A., Alexander, J., Rootwelt, H., & Aaseth, J. (2022) · Biomolecules · doi:10.3390/biom12070998 · Cited by 214
Tyrosine metabolism during interferon-alpha administration: Association with fatigue and CSF dopamine concentrations
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“Indeed, IDO inhibition or genetic deficiency is associated with resistance to behavioral changes following infection or immune activation with LPS in animal models of immune-mediated depressivelike behavior (O’Connor et al. 2009; O’Connor et al. 2008).”
Influential
A critical review of the mechanism of action for the selective serotonin reuptake inhibitors: Do these drugs possess anti-inflammatory properties and how relevant is this in the treatment of depression?
Walker, F. R. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.10.002 · Cited by 175
Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation
Parrott, J. M., Redus, L., Santana-Coelho, D., Morales, J., Gao, X., & O'Connor, J. C. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.200 · Cited by 174
The role of depressive subtypes within the neuroinflammation hypothesis of major depressive disorder
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The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress
Sahm, F., Oezen, I., Opitz, C. A., Radlwimmer, B., von Deimling, A., Ahrendt, T., Adams, S., Bode, H. B., Guillemin, G. J., Wick, W., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-3831 · Cited by 181
“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).”
BackgroundSelf-citation
IDO expression in the brain: a double-edged sword
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“In activated macrophages, the kynurenine pathway is much more effective than in activated microglia [6, 46 ], and therefore, macrophages may provide significantly more harm for”
BackgroundInfluential
Involvement of the kynurenine pathway in the pathogenesis of Parkinson's disease
Lim, C. K., Fernández-Gomez, F. J., Braidy, N., Estrada, C., Costa, C., Costa, S., Bessede, A., Fernandez-Villalba, E., Zinger, A., Herrero, M. T., et al. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.12.009 · Cited by 159
“Within the brain, QUIN is only produced by activated microglia and infiltrating macrophages (Guillemin et al., 2003b), but not by neurons or astrocytes (Guillemin et al., 2005c) (Fig.”
BackgroundInfluentialSelf-citation
Quantitation of ATP-binding cassette subfamily-A transporter gene expression in primary human brain cells
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“Neurons were prepared from the initial mixed brain cells as described previously [21,22].”
MethodSelf-citation
Bridging the gap between the immune and glutamate hypotheses of schizophrenia and major depression: Potential role of glial NMDA receptor modulators and impaired blood–brain barrier integrity
Steiner, J. H., Bogerts, B., Sarnyai, Z., Walter, M., Gos, T., Bernstein, H., & Myint, A.-M. (2011) · The World Journal of Biological Psychiatry · doi:10.3109/15622975.2011.583941 · Cited by 162
“…there is evidence for altered immunological parameters in the blood and CSF of individuals with schizophrenia and major depression, it has not (Figure 1B), but kynurenine aminotransferase and its product KYNA have been predominantly observed in astrocytes (Guillemin et al. 2000, 2001, 2005).”
Background
Microglial activation in the pathogenesis of Huntington's disease
Yang, H.-M., Yang, S., Huang, S.-S., Tang, B.-S., & Guo, J.-F. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00193 · Cited by 151
“However, the ﬁrst and rate-limiting enzyme of the kynurenine pathway, indoleamine 2,3-dioxygenase (IDO), preferentially localizes in microglia (Heyes et al., 1996), but not in astrocytes or neurons of human brain (Guillemin et al., 2005).”
Background
Current Evidence for a Role of the Kynurenine Pathway of Tryptophan Metabolism in Multiple Sclerosis
Lovelace, M. D., Varney, B., Sundaram, G., Franco, N. F., Ng, M. L., Pai, S., Lim, C. K., Guillemin, G. J., & Brew, B. J. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00246 · Cited by 161
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Host–microbiome interactions: the aryl hydrocarbon receptor as a critical node in tryptophan metabolites to brain signaling
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Stress-related regulation of the kynurenine pathway: Relevance to neuropsychiatric and degenerative disorders
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“The concentrations of quinolinic acid in the human brain are usually less than 100 nM but these can increase drastically in inflamed tissues (Guillemin et al., 2005a; Guillemin and Brew, 2002; Guidetti and Schwarcz, 2003).”
The Kynurenine Pathway is a Double-Edged Sword in Immune-Privileged Sites and in Cancer: Implications for Immunotherapy
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The Kynurenine Pathway in Brain Tumor Pathogenesis
Adams, S., Braidy, N., Bessesde, A., Brew, B. J., Grant, R., Teo, C., & Guillemin, G. J. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-0549 · Cited by 157
Self-citation
Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease
Jones, S. P., Franco, N. F., Varney, B., Sundaram, G., Brown, D. A., de Bie, J., Lim, C. K., Guillemin, G. J., & Brew, B. J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0131389 · Cited by 151
“Our group and others have shown previously that QUIN accumulates in monocytic cells following inflammatory stimulus [7, 76].”
BackgroundSelf-citation
Kynurenic acid in neurodegenerative disorders-unique neuroprotection or double-edged sword?
Ostapiuk, A., & Urbanska, E. M. (2022) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13768 · Cited by 142
Increased 3-Hydroxykynurenine serum concentrations differentiate Alzheimer’s disease patients from controls
Schwarz, M., Guillemin, G. J., Teipel, S. J., Büerger, K., & Hampel, H. J. (2012) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-012-0384-x · Cited by 141
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Central Administration of Lipopolysaccharide Induces Depressive-like Behavior in Vivo and Activates Brain Indoleamine 2,3 Dioxygenase In Murine Organotypic Hippocampal Slice Cultures
Fu, X., Zunich, S. M., O’Connor, J. C., Kavelaars, A., Dantzer, R., & Kelley, K. W. (2010) · Journal of Neuroinflammation · doi:10.1186/1742-2094-7-43 · Cited by 137
“IDO is expressed in all types of brain cells that have been studied so far, including endothelial cells, glia and neurons [18].”
Background
Kynurenines with Neuroactive and Redox Properties: Relevance to Aging and Brain Diseases
Reyes-Ocampo, J. G., Lugo-Huitrón, R., González‐Esquivel, D. F., Ugalde‐Muñiz, P., Jiménez‐Anguiano, A., Pineda, B., Pedraza‐Chaverrí, J., Rı́os, C., & de la Cruz, V. P. (2014) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2014/646909 · Cited by 149
“The vulnerability showed in human cerebral neurons may be due to the fact that the neurons can take up exogenous QUIN but can only catabolize a small amount [199] since QPRT is rapidly saturated.”
Background
Inflammation-induced depression: Its pathophysiology and therapeutic implications
Jeon, S. W., & Kim, Y.-K. (2017) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2017.10.016 · Cited by 134
“However, astrocytes lack KMO enzymes, and so the KYN-KYNA route is mainly activated, and KYNA is mainly produced (Guillemin et al., 2001; Guillemin et al., 2005).”
Background
The metabolic syndrome in schizophrenia: is inflammation a contributing cause?
Leonard, B. E., Schwarz, M., & Myint, A.-M. (2012) · Journal of Psychopharmacology · doi:10.1177/0269881111431622 · Cited by 140
“The astrocytes produce mainly the neuroprotective KYNA, whereas the microglia and macrophages produce mainly the neurotoxic 3OHK and QUIN (Guillemin et al., 2000, Guillemin et al., 2005a).”
Background
Involvement of quinolinic acid in aids dementia complex
Guillemin, G. J., Kerr, S. J., & Brew, B. J. (2005) · Neurotoxicity Research · doi:10.1007/bf03033781 · Cited by 135
“The QUIN produced by astrocytes was subsequently completely degraded (Guillemin et al., 2004).”
BackgroundResultInfluentialSelf-citation
Emerging Roles of Pericytes in the Regulation of the Neurovascular Unit in Health and Disease
Hill, J. D., Rom, S., Ramirez, S. H., & Persidsky, Y. (2014) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-014-9557-x · Cited by 136
“IDO responds to immunological signals (INFγ, LPS, TNFα) and is expressed by most human brain cells (Guillemin et al., 2005; Ball et al., 2007; Owe-Young et al., 2008).”
Indoleamine 2,3-dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX3CR1)-deficient mice
Corona, A. W., Norden, D. M., Skendelas, J. P., Huang, Y., O’Connor, J. C., Lawson, M. A., Dantzer, R., Kelley, K. W., & Godbout, J. P. (2012) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2012.08.008 · Cited by 156
“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript shifts the processing of KYN towards 3-HK and QUIN by microglia (Guillemin et al., 2005), the KAT pathway shifts the processing of KYN towards the production of kynurenic acid (KYNA) by astrocytes (Du et al., 1992;…”
Background
Challenges and Opportunities in the Discovery of New Therapeutics Targeting the Kynurenine Pathway
Dounay, A. B., Tuttle, J. B., & Verhoest, P. R. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00461 · Cited by 138
L-Kynurenine/Aryl Hydrocarbon Receptor Pathway Mediates Brain Damage After Experimental Stroke
Cuartero, M. I., Ballesteros, I., de la Parra, J., Harkin, A. L., Abautret-Daly, Á., Sherwin, E., Fernández‐Salguero, P. M., Corbí, A. L., Lizasoaín, I., & Moro, M. Á. (2014) · Circulation · doi:10.1161/circulationaha.114.011394 · Cited by 136
Neuroinflammation as an etiological trigger for depression comorbid with inflammatory bowel disease
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Kynurenine 3-Monooxygenase: An Influential Mediator of Neuropathology
Parrott, J. M., & O’Connor, J. C. (2015) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2015.00116 · Cited by 125
“While astrocytes have the capability to clear extracellular QA and metabolize it to nicotinic acid, they are not able to produce it (22).”
Background
Effects of inflammation on the kynurenine pathway in schizophrenia—a systematic review
Pedraz-Petrozzi, B., Elyamany, O., Rummel, C., & Mulert, C. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-1721-z · Cited by 119
Neuropsychiatric disorders related to interferon and interleukins treatment
Myint, A. M., Schwarz, M. J., Steinbusch, H. W. M., & Leonard, B. E. (2009) · Metabolic Brain Disease · doi:10.1007/s11011-008-9114-5 · Cited by 116
“The astrocytes were shown to produce mainly kynurenic acid whereas microglia and macrophages produced mainly quinolinic acid ( Guillemin et al. 2000, 2001, 2005a ).”
Background
Imbalanced Kynurenine Pathway in Schizophrenia
Kegel, M. E., Bhat, M., Skogh, E., Samuelsson, M., Lundberg, K., Dahl, M., Sellgren, C. M., Schwieler, L., Engberg, G., Schuppe‐Koistinen, I., et al. (2014) · International Journal of Tryptophan Research · doi:10.4137/ijtr.s16800 · Cited by 122
Neuroprotective effects of naturally occurring polyphenols on quinolinic acid‐induced excitotoxicity in human neurons
Braidy, N., Grant, R., Adams, S., & Guillemin, G. J. (2009) · FEBS Journal · doi:10.1111/j.1742-4658.2009.07487.x · Cited by 110
“For example, QUIN is found at high concentrations in immuno-active amyloid plaques in the AD brain [1, 2, 29].”
BackgroundSelf-citation
Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge
Parrott, J. M., Redus, L., & O’Connor, J. C. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0590-y · Cited by 112
“Microglia express KMO (not KATs) that metabolizes kynurenine along the neurotoxic branch, leading to the potential formation of several neurotoxic metabolites [65, 66].”
Background
Modulation of immunity by tryptophan microbial metabolites
Li, S. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1209613 · Cited by 104
Correlation between plasma and CSF concentrations of kynurenine pathway metabolites in Alzheimer's disease and relationship to amyloid-β and tau
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“Although numbers of perivascular and infiltrating macrophages will be much lower than activated microglia present in the brain, it is known that activated macrophages produce 40-fold more QUIN than activated microglia (Guillemin et al., 2004).”
BackgroundSelf-citation
Tryptophan degradation in autoimmune diseases
Opitz, C. A., Wick, W., Steinman, L., & Platten, M. (2007) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-7140-9 · Cited by 102
Inflammation, insulin resistance and neuroprogression in depression
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“Under non-inflammatory conditions, the end product of kynureninemetabolism is kynurenic acid, but following the activation of the microglia by stress or inflammation, the neurodegenerative pathway predominates (Guillemin et al., 2005).”
Background
Extracellular Vesicles Released by Glioblastoma Cells Stimulate Normal Astrocytes to Acquire a Tumor-Supportive Phenotype Via p53 and MYC Signaling Pathways
Hallal, S. M., Mallawaaratchy, D. M., Wei, H., Ebrahimkhani, S., Stringer, B. W., Day, B. W., Boyd, A., Guillemin, G. J., Buckland, M. E., & Alexander, K. L. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1385-1 · Cited by 119
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Spatio-temporal differences in the profile of murine brain expression of proinflammatory cytokines and indoleamine 2,3-dioxygenase in response to peripheral lipopolysaccharide administration
André, C., O’Connor, J. C., Kelley, K. W., Lestage, J., Dantzer, R., & Castanon, N. (2008) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2008.06.011 · Cited by 116
“It is expressed in human and mouse macrophages and dendritic cells, as well as in brain endothelial cells, astrocytes, microglia and neurons (Carlin et al., 1989; Guillemin et al., 2005; Kwidzinski et al., 2005).”
Background
M. tuberculosis Induces Potent Activation of IDO-1, but This Is Not Essential for the Immunological Control of Infection
Blumenthal, A., Nagalingam, G., Huch, J. H., Walker, L., Guillemin, G. J., Smythe, G. A., Ehrt, S., Britton, W. J., & Saunders, B. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037314 · Cited by 105
“This is in concordance with a previous observation showing differences in the production of quinolinic acid by different macrophage types (MDM compared to microglia), despite comparable levels of IDO1 mRNA expression [22].”
ResultSelf-citation

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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