621 The Association of Interferon with Kynurenine/Tryptophan Pathway Activation in Systemic Lupus Erythematosus

BackgroundCognitive 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.MethodsWe 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.ResultsSerum KYN/TRP and QA/KA ratios were higher in SLE versus HC (p