Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
05
10
2017
accepted:
05
03
2019
revised:
22
02
2019
pubmed:
4
4
2019
medline:
16
3
2021
entrez:
4
4
2019
Statut:
ppublish
Résumé
The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain samples from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup. KAT mRNAs significantly correlated with mRNA for glial fibrillary acidic protein in patients. In plasma, the high cytokine schizophrenia subgroup displayed an elevated KYN/TRP ratio, which correlated inversely with attention and dorsolateral prefrontal cortex (DLPFC) volume. This study provides further evidence for the role of inflammation in a subgroup of patients with schizophrenia and suggests a molecular mechanism through which inflammation could lead to schizophrenia. Proinflammatory cytokines may elicit conversion of TRP to KYN in the periphery and increase the N-methyl-D-aspartate receptor antagonist KYNA via increased KAT mRNA and possibly more enzyme synthesis activity in brain astrocytes, leading to DLPFC volume loss, and attention impairment in schizophrenia.
Identifiants
pubmed: 30940904
doi: 10.1038/s41380-019-0401-9
pii: 10.1038/s41380-019-0401-9
pmc: PMC7577855
doi:
Substances chimiques
Cytokines
0
Inflammation Mediators
0
Kynurenine
343-65-7
Kynurenic Acid
H030S2S85J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2860-2872Références
Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.
pmcid: 4112379
doi: 10.1038/nature13595
Fillman SG, Cloonan N, Catts VS, Miller LC, Wong J, McCrossin T, et al. Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry. 2013;18:206–14.
doi: 10.1038/mp.2012.110
pubmed: 22869038
Muller N, Myint AM, Krause D, Weidinger E, Schwarz MJ. Anti-inflammatory treatment in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:146–53.
pubmed: 23178230
doi: 10.1016/j.pnpbp.2012.11.008
Fillman SG, Sinclair D, Fung SJ, Webster MJ, Shannon Weickert C. Markers of inflammation and stress distinguish subsets of individuals with schizophrenia and bipolar disorder. Transl Psychiatry. 2014;4:e365.
pubmed: 24569695
pmcid: 3944638
doi: 10.1038/tp.2014.8
Fillman SG, Weickert TW, Lenroot RK, Catts SV, Bruggemann JM, Catts VS, et al. Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca’s area volume. Mol Psychiatry. 2016;21:1090–8.
pubmed: 26194183
doi: 10.1038/mp.2015.90
Prendergast GC, Chang MY, Mandik-Nayak L, Metz R, Muller AJ. Indoleamine 2,3-dioxygenase as a modifier of pathogenic inflammation in cancer and other inflammation-associated diseases. Curr Med Chem. 2011;18:2257–62.
pubmed: 21517753
pmcid: 4384691
doi: 10.2174/092986711795656072
Alberati-Giani D, Ricciardi-Castagnoli P, Kohler C, Cesura AM. Regulation of the kynurenine metabolic pathway by interferon-gamma in murine cloned macrophages and microglial cells. J Neurochem. 1996;66:996–1004.
pubmed: 8769859
doi: 10.1046/j.1471-4159.1996.66030996.x
Zunszain PA, Anacker C, Cattaneo A, Choudhury S, Musaelyan K, Myint AM, et al. Interleukin-1beta: a new regulator of the kynurenine pathway affecting human hippocampal neurogenesis. Neuropsychopharmacology. 2012;37:939–49.
pubmed: 22071871
doi: 10.1038/npp.2011.277
Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci. 2012;13:465–77.
pubmed: 22678511
pmcid: 3681811
doi: 10.1038/nrn3257
Thomas SR, Stocker R. Redox reactions related to indoleamine 2,3-dioxygenase and tryptophan metabolism along the kynurenine pathway. Redox Rep. 1999;4:199–220.
pubmed: 10731095
doi: 10.1179/135100099101534927
Ren S, Correia MA. Heme: a regulator of rat hepatic tryptophan 2,3-dioxygenase? Arch Biochem Biophys. 2000;377:195–203.
pubmed: 10775460
doi: 10.1006/abbi.2000.1755
Guidetti P, Amori L, Sapko MT, Okuno E, Schwarcz R. Mitochondrial aspartate aminotransferase: a third kynurenate-producing enzyme in the mammalian brain. J Neurochem. 2007;102:103–11.
pubmed: 17442055
doi: 10.1111/j.1471-4159.2007.04556.x
Chiarugi A, Carpenedo R, Molina MT, Mattoli L, Pellicciari R, Moroni F. Comparison of the neurochemical and behavioral effects resulting from the inhibition of kynurenine hydroxylase and/or kynureninase. J Neurochem. 1995;65:1176–83.
pubmed: 7643095
doi: 10.1046/j.1471-4159.1995.65031176.x
Carpenedo R, Pittaluga A, Cozzi A, Attucci S, Galli A, Raiteri M, et al. Presynaptic kynurenate-sensitive receptors inhibit glutamate release. Eur J Neurosci. 2001;13:2141–7.
pubmed: 11422455
doi: 10.1046/j.0953-816x.2001.01592.x
Rassoulpour A, Wu HQ, Ferre S, Schwarcz R. Nanomolar concentrations of kynurenic acid reduce extracellular dopamine levels in the striatum. J Neurochem. 2005;93:762–5.
pubmed: 15836634
doi: 10.1111/j.1471-4159.2005.03134.x
Hilmas C, Pereira EF, Alkondon M, Rassoulpour A, Schwarcz R, Albuquerque EX. The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neurosci. 2001;21:7463–73.
pubmed: 11567036
pmcid: 6762893
doi: 10.1523/JNEUROSCI.21-19-07463.2001
Perkins MN, Stone TW. An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res. 1982;247:184–7.
pubmed: 6215086
doi: 10.1016/0006-8993(82)91048-4
Javitt DC, Zukin SR, Heresco-Levy U, Umbricht D. Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia. Schizophr Bull. 2012;38:958–66.
pubmed: 22987851
pmcid: 3446214
doi: 10.1093/schbul/sbs069
Schwarcz R, Rassoulpour A, Wu HQ, Medoff D, Tamminga CA, Roberts RC. Increased cortical kynurenate content in schizophrenia. Biol Psychiatry. 2001;50:521–30.
pubmed: 11600105
doi: 10.1016/S0006-3223(01)01078-2
Wonodi I, Stine OC, Sathyasaikumar KV, Roberts RC, Mitchell BD, Hong LE, et al. Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes. Arch Gen Psychiatry. 2011;68:665–74.
pubmed: 21727251
doi: 10.1001/archgenpsychiatry.2011.71
Linderholm KR, Skogh E, Olsson SK, Dahl ML, Holtze M, Engberg G, et al. Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia. Schizophr Bull. 2012;38:426–32.
pubmed: 20729465
doi: 10.1093/schbul/sbq086
Schwieler L, Larsson MK, Skogh E, Kegel ME, Orhan F, Abdelmoaty S, et al. Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia--significance for activation of the kynurenine pathway. J Psychiatry Neurosci. 2015;40:126–33.
pubmed: 25455350
pmcid: 4354818
doi: 10.1503/jpn.140126
Wang AK, Miller BJ. Meta-analysis of cerebrospinal fluid cytokine and tryptophan catabolite alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder, and depression. Schizophr Bull. 2018;44:75–83.
pubmed: 28338954
doi: 10.1093/schbul/sbx035
Lavebratt C, Olsson S, Backlund L, Frisen L, Sellgren C, Priebe L, et al. The KMO allele encoding Arg452 is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and reduced KMO expression. Mol Psychiatry. 2014;19:334–41.
pubmed: 23459468
doi: 10.1038/mp.2013.11
Erhardt S, Schwieler L, Imbeault S, Engberg G. The kynurenine pathway in schizophrenia and bipolar disorder. Neuropharmacology. 2017;112(Pt B):297–306.
pubmed: 27245499
doi: 10.1016/j.neuropharm.2016.05.020
Chiappelli J, Rowland LM, Notarangelo FM, Wijtenburg SA, Thomas MAR, Pocivavsek A, et al. Salivary kynurenic acid response to psychological stress: inverse relationship to cortical glutamate in schizophrenia. Neuropsychopharmacology. 2018;43:1706–11.
pubmed: 29728648
pmcid: 6006286
doi: 10.1038/s41386-018-0072-2
Chiappelli J, Pocivavsek A, Nugent KL, Notarangelo FM, Kochunov P, Rowland LM, et al. Stress-induced increase in kynurenic acid as a potential biomarker for patients with schizophrenia and distress intolerance. JAMA Psychiatry. 2014;71:761–8.
pubmed: 24806441
pmcid: 4219570
doi: 10.1001/jamapsychiatry.2014.243
Guillemin GJ, Kerr SJ, Smythe GA, Smith DG, Kapoor V, Armati PJ, et al. Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection. J Neurochem. 2001;78:842–53.
pubmed: 11520905
doi: 10.1046/j.1471-4159.2001.00498.x
Notarangelo FM, Wilson EH, Horning KJ, Thomas MA, Harris TH, Fang Q, et al. Evaluation of kynurenine pathway metabolism in Toxoplasma gondii-infected mice: implications for schizophrenia. Schizophr Res. 2014;152:261–7.
pubmed: 24345671
doi: 10.1016/j.schres.2013.11.011
Chiappelli J, Postolache TT, Kochunov P, Rowland LM, Wijtenburg SA, Shukla DK, et al. Tryptophan metabolism and white matter integrity in schizophrenia. Neuropsychopharmacology. 2016;41:2587–95.
pubmed: 27143602
pmcid: 4987857
doi: 10.1038/npp.2016.66
Barry S, Clarke G, Scully P, Dinan TG. Kynurenine pathway in psychosis: evidence of increased tryptophan degradation. J Psychopharmacol. 2009;23:287–94.
pubmed: 18562404
doi: 10.1177/0269881108089583
Okusaga O, Fuchs D, Reeves G, Giegling I, Hartmann AM, Konte B, et al. Kynurenine and tryptophan levels in patients with schizophrenia and elevated antigliadin immunoglobulin G antibodies. Psychosom Med. 2016;78:931–9.
pubmed: 27359171
pmcid: 5338470
doi: 10.1097/PSY.0000000000000352
Weickert CS, Sheedy D, Rothmond DA, Dedova I, Fung S, Garrick T, et al. Selection of reference gene expression in a schizophrenia brain cohort. Aust NZ J Psychiatry. 2010;44:59–70.
doi: 10.3109/00048670903393662
First MB. Structured Clinical Interview for DSM-IV-TR Axis I Disorders: SCID-I. New York: Biometrics Research Department, State Psychiatric Institute; 2007.
Lim CK, Bilgin A, Lovejoy DB, Tan V, Bustamante S, Taylor BV, et al. Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression. Sci Rep. 2017;7:41473.
pubmed: 28155867
pmcid: 5290739
doi: 10.1038/srep41473
Felger JC, Haroon E, Patel TA, Goldsmith DR, Wommack EC, Woolwine BJ, et al. What does plasma CRP tell us about peripheral and central inflammation in depression? Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0096-3 .
Moore L, Kyaw M, Vercammen A, Lenroot R, Kulkarni J, Curtis J, et al. Serum testosterone levels are related to cognitive function in men with schizophrenia. Psychoneuroendocrinology. 2013;38:1717–28.
pubmed: 23490072
doi: 10.1016/j.psyneuen.2013.02.007
Sathyasaikumar KV, Stachowski EK, Wonodi I, Roberts RC, Rassoulpour A, McMahon RP, et al. Impaired kynurenine pathway metabolism in the prefrontal cortex of individuals with schizophrenia. Schizophr Bull. 2011;37:1147–56.
pubmed: 21036897
doi: 10.1093/schbul/sbq112
Gur RE, Cowell PE, Latshaw A, Turetsky BI, Grossman RI, Arnold SE, et al. Reduced dorsal and orbital prefrontal gray matter volumes in schizophrenia. Arch Gen Psychiatry. 2000;57:761–8.
pubmed: 10920464
doi: 10.1001/archpsyc.57.8.761
Fornito A, Yucel M, Patti J, Wood SJ, Pantelis C. Mapping grey matter reductions in schizophrenia: an anatomical likelihood estimation analysis of voxel-based morphometry studies. Schizophr Res. 2009;108:104–13.
pubmed: 19157788
doi: 10.1016/j.schres.2008.12.011
Weinberg D, Lenroot R, Jacomb I, Allen K, Bruggemann J, Wells R, et al. Cognitive subtypes of schizophrenia characterized by differential brain volumetric reductions and cognitive decline. JAMA Psychiatry. 2016;73:1251–9.
pubmed: 27829096
doi: 10.1001/jamapsychiatry.2016.2925
Boerrigter D, Weickert TW, Lenroot R, O’Donnell M, Galletly C, Liu D, et al. Using blood cytokine measures to define high inflammatory biotype of schizophrenia and schizoaffective disorder. J Neuroinflamm. 2017;14:188.
doi: 10.1186/s12974-017-0962-y
Weickert CS, Fung SJ, Catts VS, Schofield PR, Allen KM, Moore LT, et al. Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Mol Psychiatry. 2013;18:1185–92.
pubmed: 23070074
doi: 10.1038/mp.2012.137
Kozak R, Campbell BM, Strick CA, Horner W, Hoffmann WE, Kiss T, et al. Reduction of brain kynurenic acid improves cognitive function. J Neurosci. 2014;34:10592–602.
pubmed: 25100593
pmcid: 6802596
doi: 10.1523/JNEUROSCI.1107-14.2014
Myint AM, Schwarz MJ, Verkerk R, Mueller HH, Zach J, Scharpe S, et al. Reversal of imbalance between kynurenic acid and 3-hydroxykynurenine by antipsychotics in medication-naive and medication-free schizophrenic patients. Brain Behav Immun. 2011;25:1576–81.
pubmed: 21620952
doi: 10.1016/j.bbi.2011.05.005
Condray R, Dougherty GG Jr., Keshavan MS, Reddy RD, Haas GL, Montrose DM, et al. 3-Hydroxykynurenine and clinical symptoms in first-episode neuroleptic-naive patients with schizophrenia. Int J Neuropsychopharmacol. 2011;14:756–67.
pubmed: 21275080
doi: 10.1017/S1461145710001689
Yao JK, Dougherty GG Jr., Reddy RD, Keshavan MS, Montrose DM, Matson WR, et al. Altered interactions of tryptophan metabolites in first-episode neuroleptic-naive patients with schizophrenia. Mol Psychiatry. 2010;15:938–53.
pubmed: 19401681
doi: 10.1038/mp.2009.33
Chiappelli J, Notarangelo FM, Pocivavsek A, Thomas MAR, Rowland LM, Schwarcz R, et al. Influence of plasma cytokines on kynurenine and kynurenic acid in schizophrenia. Neuropsychopharmacology. 2018;43:1675–80.
pubmed: 29520060
pmcid: 6006321
doi: 10.1038/s41386-018-0038-4
Zavitsanou K, Lim CK, Purves-Tyson T, Karl T, Kassiou M, Banister SD, et al. Effect of maternal immune activation on the kynurenine pathway in preadolescent rat offspring and on MK801-induced hyperlocomotion in adulthood: amelioration by COX-2 inhibition. Brain Behav Immun. 2014;41:173–81.
pubmed: 24878170
doi: 10.1016/j.bbi.2014.05.011
Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, Vogt G, et al. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry. 2010;15:393–403.
pubmed: 19918244
doi: 10.1038/mp.2009.116
Guidetti P, Hoffman GE, Melendez-Ferro M, Albuquerque EX, Schwarcz R. Astrocytic localization of kynurenine aminotransferase II in the rat brain visualized by immunocytochemistry. Glia. 2007;55:78–92.
pubmed: 17024659
doi: 10.1002/glia.20432
Catts VS, Wong J, Fillman SG, Fung SJ, Weickert CS. Increased expression of astrocyte markers in schizophrenia: association with neuroinflammation. Aust NZ J Psychiatry. 2014;48:722–34.
Weickert CS, Weickert TW, Pillai A, Buckley PF. Biomarkers in schizophrenia: a brief conceptual consideration. Dis Markers. 2013;35:3–9.
pubmed: 24167344
pmcid: 3774970
doi: 10.1155/2013/510402
Cannon TD, Chung Y, He G, Sun D, Jacobson A, van Erp TG, et al. Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biol Psychiatry. 2015;77:147–57.
pubmed: 25034946
doi: 10.1016/j.biopsych.2014.05.023
Volk DW, Chitrapu A, Edelson JR, Roman KM, Moroco AE, Lewis DA. Molecular mechanisms and timing of cortical immune activation in schizophrenia. Am J Psychiatry. 2015;172:1112–21.
pubmed: 26133963
pmcid: 5063256
doi: 10.1176/appi.ajp.2015.15010019
Birnbaum R, Jaffe AE, Chen Q, Shin JH, BrainSeq C, Kleinman JE, et al. Investigating the neuroimmunogenic architecture of schizophrenia. Mol Psychiatry. 2018;23:1251–60.
pubmed: 28485405
doi: 10.1038/mp.2017.89
Bland JM, Altman DG. Multiple significance tests: the Bonferroni method. BMJ. 1995;310:170.
pubmed: 7833759
pmcid: 2548561
doi: 10.1136/bmj.310.6973.170