Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons
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 activity likely follows innate immune responses to VEEV TC-83 infection and serves as the initiation step of tryptophan metabolism in the CNS.
“further suggesting that IDO activity likely follows innate immune responses to VEEV TC-83 infection and serves as the initiation step of TRP metabolism in the CNS [43].”
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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).”
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“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-citationIDO expression in the brain: a double-edged sword
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BackgroundInfluentialInvolvement of the kynurenine pathway in the pathogenesis of Parkinson's disease
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“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.”
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“…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).”
BackgroundMicroglial 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 · see citing works
“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).”
BackgroundCurrent 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 154 · see citing works
Self-citationMa, N., He, T., Johnston, L. J., & Ma, X. (2020) · Gut Microbes · doi:10.1080/19490976.2020.1758008 · Cited by 158 · see citing works
O’Farrell, K., & Harkin, A. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.12.004 · Cited by 161 · see citing works
“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).”
Routy, J., Routy, B., Graziani, G. M., & Mehraj, V. (2016) · International Journal of Tryptophan Research · doi:10.4137/ijtr.s38355 · Cited by 171 · see citing works
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 154 · see citing works
Self-citationJones, 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 142 · see citing works
“Our group and others have shown previously that QUIN accumulates in monocytic cells following inflammatory stimulus [7, 76].”
BackgroundSelf-citationKynurenic 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 · see citing works
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 · see citing works
Self-citationFu, 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 130 · see citing works
“IDO is expressed in all types of brain cells that have been studied so far, including endothelial cells, glia and neurons [18].”
BackgroundKynurenines with Neuroactive and Redox Properties: Relevance to Aging and Brain Diseases
Ocampo, J. R., Huitrón, R. L., González-Esquivel, D., Ugalde-Muñiz, P., Jiménez-Anguiano, A., Pineda, B., Pedraza-Chaverri, J., Ríos, C., & de la Cruz, V. P. (2014) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2014/646909 · Cited by 136 · see citing works
“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.”
BackgroundInflammation-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 · see citing works
“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).”
BackgroundThe 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 134 · see citing works
“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).”
BackgroundInvolvement 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 · see citing works
“The QUIN produced by astrocytes was subsequently completely degraded (Guillemin et al., 2004).”
BackgroundResultInfluentialSelf-citationEmerging 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 134 · see citing works
“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).”
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 150 · see citing works
“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;…”
BackgroundChallenges 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 · see citing works
L-Kynurenine/Aryl Hydrocarbon Receptor Pathway Mediates Brain Damage After Experimental Stroke
Cuartero, M., Ballesteros, I., de la Parra, J., Harkin, A., Abautret-Daly, Á., Sherwin, E., Fernández-Salguero, P., Corbí, Á., Lizasoaín, I., & Moro, M. A. (2014) · Circulation · doi:10.1161/circulationaha.114.011394 · Cited by 125 · see citing works
Neuroinflammation as an etiological trigger for depression comorbid with inflammatory bowel disease
Craig, C. F., Filippone, R. T., Stavely, R., Bornstein, J. C., Apostolopoulos, V., & Nurgali, K. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02354-1 · Cited by 124 · see citing works
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 123 · see citing works
“While astrocytes have the capability to clear extracellular QA and metabolize it to nicotinic acid, they are not able to produce it (22).”
BackgroundEffects 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 · see citing works
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 · see citing works
“The astrocytes were shown to produce mainly kynurenic acid whereas microglia and macrophages produced mainly quinolinic acid ( Guillemin et al. 2000, 2001, 2005a ).”
BackgroundImbalanced Kynurenine Pathway in Schizophrenia
Kegel, M. E., Bhat, M., Skogh, E., Samuelsson, M., Lundberg, K., Dahl, M., Sellgren, C., Schwieler, L., Engberg, G., Schuppe-Koistinen, I., et al. (2014) · International Journal of Tryptophan Research · doi:10.4137/ijtr.s16800 · Cited by 116 · see citing works
Braidy, N., Grant, R., Adams, S., & Guillemin, G. (2010) · The FEBS Journal · doi:10.1111/j.1742-4658.2009.07487.x · Cited by 113 · see citing works
“For example, QUIN is found at high concentrations in immuno-active amyloid plaques in the AD brain [1, 2, 29].”
BackgroundSelf-citationParrott, J. M., Redus, L., & O’Connor, J. C. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0590-y · Cited by 112 · see citing works
“Microglia express KMO (not KATs) that metabolizes kynurenine along the neurotoxic branch, leading to the potential formation of several neurotoxic metabolites [65, 66].”
BackgroundModulation of immunity by tryptophan microbial metabolites
Li, S. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1209613 · Cited by 101 · see citing works
Jacobs, K. R., Lim, C. K., Blennow, K., Zetterberg, H., Chatterjee, P., Martins, R. N., Brew, B. J., Guillemin, G. J., & Lovejoy, D. B. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.03.015 · Cited by 127 · see citing works
“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-citationTryptophan 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 100 · see citing works
Inflammation, insulin resistance and neuroprogression in depression
Leonard, B. E., & Wegener, G. (2019) · Acta Neuropsychiatrica · doi:10.1017/neu.2019.17 · Cited by 120 · see citing works
“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).”
BackgroundHallal, 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 114 · see citing works
Self-citationAndré, 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 111 · see citing works
“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).”
BackgroundBlumenthal, 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 · see citing works
“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.
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2004-07-06
- Volume
- 49
- Issue
- 1
- Pages
- 15-23
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- 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
- 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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