Background Cognitive dysfunction (CD) is highly prevalent in systemic lupus erythematosus (SLE) with significant impact on quality of life, yet SLE-mediated mechanisms for CD remain poorly understood. Quinolinic acid (QA), a metabolite of the kynurenine (KYN)/tryptophan (TRP) pathway, is a N-methyl-D-aspartate receptor (NMDAR) agonist that can cause excessive glutamatergic excitotoxicity to neurons,1 while kynurenic acid (KA) is an NMDAR antagonist with potential to protect neurons from excitotoxic damage (figure 1).1 Type I and II interferon (IFN) contributes to SLE pathogenesis and stimulates the KYN/TRP pathway, producing an elevated QA/KA ratio, a potential neurotoxic imbalance. We determined whether peripheral blood IFN- stimulated gene (ISG) expression associates with elevated serum KYN/TRP and QA/KA ratios in SLE.
Methods We measured ISG expression (whole blood RNA sequencing) and serum metabolite ratios (High Performance Liquid Chromatography) in 72 SLE subjects and 73 healthy controls (HC). We identified ISG based on published gene sets from Arazi et al2 (“ISG-A,” N=110 ISG), Chiche et al3 (“19 type I ISG” more responsive to type I than type II IFN), and the Interferome database.4 We derived individual IFN scores to analyze associations with metabolite ratios and clinical parameters. These analyses were performed in SLE subgroups based on level of ISG expression (“IFN high”, “IFN low” and “IFN similar to HC”) and, using CIBERSORTx, according to the level of monocyte-associated gene expression.
Results Serum KYN/TRP and QA/KA ratios were higher in SLE versus HC (p<0.01) (table 1). SLE subjects were racially diverse, reflective of disease demographics, with a wide range of disease activity (SLEDAI scores ranging 0-29) and medication use. There were no demographic differences between SLE and HC. Nine hundred thirty-three genes were differentially expressed ≥2-fold in SLE versus HC, with 762 genes overexpressed and 171 underexpressed (p<0.05). Seventy of the top 100 most highly variant genes were ISG. Of the 762 overexpressed genes in SLE subjects, 144 positively correlated with KYN/TRP ratios (p<0.05) and 71 (49%) of these were ISG. Similarly, 81 of the 762 overexpressed genes positively correlated with QA/KA ratios in SLE subjects (p<0.05), and 38 (47%) of these were ISG. In 36 “IFN high” SLE subjects, IFN scores correlated with KYN/TRP ratios (p<0.01), but not with QA/KA ratios (table 2). Of these 36 “IFN high” SLE subjects, 23 had high monocyte-associated gene expression and in this subgroup, the IFN scores correlated with both KYN/TRP and QA/KA ratios (p<0.05) (table 3).
Conclusions SLE subjects demonstrate increased KYN/TRP pathway metabolite ratios, and high ISG expression correlated with elevated KYN/TRP ratios, suggesting IFN-mediated KYN/TRP pathway activation. High ISG expression also correlated with QA/KA ratios in SLE subjects with high monocyte-associated gene expression, suggesting that KYN/TRP pathway activation may be particularly important in monocytes. These results need validation, which may aid in determining which subset of patients may benefit from therapeutics directed at the IFN or KYN/TRP pathways to ameliorate a potentially neurotoxic QA/KA imbalance.
Schwarcz R and Stone TW. The kynurenine pathway and the brain: Challenges, controversies and promises. Neuropharmacology 2017;112:237-247.
Arazi A, Rao DA, Berthier CC, et al. The immune cell landscape in kidneys of patients with lupus nephritis. Nat Immunol 2019;20:902-914.
Chiche L, Jourde-Chiche N, Whalen E, et al. Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures. Arthritis Rheumatol 2014;66:1583-95.
Rusinova I, Forster S, Yu S, et al. Interferome v2.0: an updated database of annotated interferon- regulated genes. Nucleic Acids Res 2013;41:D1040-6.
Lugo-Huitron R, Ugalde Muniz P, Pineda B, et al. Quinolinic acid: an endogenous neurotoxin with multiple targets. Oxid Med Cell Longev 2013;2013:104024.
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