Quinolinic acid, a kynurenine/tryptophan pathway metabolite, associates with impaired cognitive test performance in systemic lupus erythematosus.
autoimmunity
cytokines
inflammation
lupus erythematosus
systemic
Journal
Lupus science & medicine
ISSN: 2053-8790
Titre abrégé: Lupus Sci Med
Pays: England
ID NLM: 101633705
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
12
08
2021
accepted:
12
10
2021
entrez:
23
10
2021
pubmed:
24
10
2021
medline:
3
11
2021
Statut:
ppublish
Résumé
Interferon-alpha, an important contributor to SLE pathogenesis, induces the enzyme indoleamine 2,3-dioxygenase in the kynurenine/tryptophan (KYN/TRP) pathway. This leads to a potentially neurotoxic imbalance in the KYN/TRP pathway metabolites, quinolinic acid (QA), an N-methyl D-aspartate glutamatergic receptor (NMDAR) agonist, and kynurenic acid (KA), an NMDAR antagonist. We determined whether QA/KA ratios associate with cognitive dysfunction (CD) and depression in SLE. This cross-sectional study included 74 subjects with SLE and 74 healthy control (HC) subjects; all without history of neuropsychiatric disorders. Serum metabolite levels (KYN, TRP, QA, KA) were measured concurrently with assessments of cognition (Automated Neuropsychological Assessment Metrics (ANAM), 2×2 array), mood and pain, and compared between SLE and HC. Multivariable modelling in SLE was used to evaluate associations of metabolites with cognitive performance and depression. Serum KYN/TRP and QA/KA ratios were elevated in SLE versus HC (p<0.0001). SLE performed worse than HC on four of five ANAM tests (all p≤0.02) and the 2×2 array (p<0.01), and had higher depression scores (p<0.01). In SLE, elevated QA/KA ratios correlated with poor performance on Match to Sample (MTS), a working memory and visuospatial processing task (p<0.05). Subjects with SLE with elevated QA/KA ratios also had slightly higher odds of depression, but this did not reach significance (p=0.09). Multivariable modelling in SLE confirmed an association between QA/KA ratios and poor MTS performance when considering potentially confounding factors (p<0.05). Elevated serum KYN/TRP and QA/KA ratios confirm KYN/TRP pathway activation in SLE. The novel association between increased QA/KA ratios and poor cognitive performance supports further study of this pathway as a potential biomarker or therapeutic target for SLE-mediated CD.
Identifiants
pubmed: 34686589
pii: 8/1/e000559
doi: 10.1136/lupus-2021-000559
pmc: PMC8543639
pii:
doi:
Substances chimiques
Kynurenine
343-65-7
Tryptophan
8DUH1N11BX
Quinolinic Acid
F6F0HK1URN
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
Références
Discov Med. 2010 Mar;9(46):173-8
pubmed: 20350481
Biol Psychol. 2016 Oct;120:10-20
pubmed: 27481545
Brain Behav Immun. 2020 Jan;83:153-162
pubmed: 31606477
J Biol Chem. 1993 Jul 25;268(21):15496-503
pubmed: 8340378
Hematology Am Soc Hematol Educ Program. 2007;:363-70
pubmed: 18024652
Curr Opin Neurol. 2020 Jun;33(3):353-361
pubmed: 32349105
Rheumatology (Oxford). 2017 Jan;56(1):77-86
pubmed: 28028157
Mol Psychiatry. 2010 Apr;15(4):393-403
pubmed: 19918244
J Neuroinflammation. 2016 Feb 29;13(1):51
pubmed: 26925576
Brain Sci. 2017 Apr 27;7(5):
pubmed: 28448453
J Neurochem. 2002 Jul;82(2):258-68
pubmed: 12124427
Arthritis Rheum. 2012 Sep;64(9):2937-46
pubmed: 22549432
JCI Insight. 2019 Jan 10;4(1):
pubmed: 30626758
Curr Top Behav Neurosci. 2017;31:249-267
pubmed: 27221627
Arch Gerontol Geriatr. 2016 Jan-Feb;62:118-24
pubmed: 26388436
Arthritis Rheum. 2011 Oct;63(10):3048-57
pubmed: 21618460
Arthritis Rheum. 2013 May;65(5):1313-8
pubmed: 23400548
Mol Med. 2011;17(11-12):1349-56
pubmed: 21953419
Int J Tryptophan Res. 2009 Mar 23;2:45-60
pubmed: 20651948
Clin Exp Rheumatol. 2005 Sep-Oct;23(5 Suppl 39):S120-32
pubmed: 16273796
Folia Neuropathol. 2018;56(1):14-20
pubmed: 29663736
Nat Rev Neurosci. 2011 Apr;12(4):217-30
pubmed: 21415848
Arthritis Rheum. 2012 Aug;64(8):2677-86
pubmed: 22553077
Rheumatol Ther. 2021 Jun;8(2):651-679
pubmed: 33993432
Neuropharmacology. 2017 Jan;112(Pt B):237-247
pubmed: 27511838
J Rheumatol. 1996 May;23(5):850-5
pubmed: 8724297
Arthritis Rheum. 1997 May;40(5):809-13
pubmed: 9153540
Lupus. 1999;8(8):685-91
pubmed: 10568907
Lupus Sci Med. 2019 Aug 13;6(1):e000270
pubmed: 31497305
Clin Neuropsychol. 2000 Aug;14(3):287-94
pubmed: 11262703
Brain. 2004 May;127(Pt 5):1047-60
pubmed: 15013955
Arthritis Rheum. 1997 Sep;40(9):1725
pubmed: 9324032
Transpl Immunol. 2011 Sep;25(2-3):119-23
pubmed: 21742032
BMC Musculoskelet Disord. 2010 Jan 23;11:13
pubmed: 20096132
Adv Exp Med Biol. 1999;467:571-7
pubmed: 10721102
Br J Pharmacol. 2013 Jul;169(6):1211-27
pubmed: 23647169
Adv Med Sci. 2010;55(2):204-11
pubmed: 20639188
Neurotox Res. 2010 Aug;18(2):132-42
pubmed: 19921535
Arthritis Rheumatol. 2019 Sep;71(9):1413-1425
pubmed: 31102496
Neurobiol Aging. 2019 Aug;80:11-20
pubmed: 31055163
Lupus Sci Med. 2018 May 23;5(1):e000254
pubmed: 29868176
J Neurochem. 1991 Jun;56(6):2007-17
pubmed: 1827495
J Alzheimers Dis. 2017;60(2):495-504
pubmed: 28869479
Eur J Pharmacol. 2017 Sep 5;810:163-173
pubmed: 28688912
Sci Rep. 2016 Nov 07;6:36489
pubmed: 27819338
PLoS One. 2015 Apr 21;10(4):e0125109
pubmed: 25897671
J Neuroinflammation. 2020 Nov 12;17(1):340
pubmed: 33183319
Metabolomics. 2015;11(5):1157-1174
pubmed: 26366134
J Neuroinflammation. 2010 Feb 03;7:10
pubmed: 20128908
J Neural Transm Suppl. 1979;(15):81-92
pubmed: 290764
FEBS Open Bio. 2012 Aug 17;2:241-5
pubmed: 23650606
Oxid Med Cell Longev. 2013;2013:104024
pubmed: 24089628
Curr Rheumatol Rep. 2017 Aug;19(8):48
pubmed: 28718063
Lupus Sci Med. 2015 Mar 28;2(1):e000074
pubmed: 25861456