Associations between circulating interferon and kynurenine/tryptophan pathway metabolites: support for a novel potential mechanism for cognitive dysfunction in SLE

Abstract

Objective: Quinolinic acid (QA), a kynurenine (KYN)/tryptophan (TRP) pathway metabolite, is an N-methyl-D-aspartate receptor agonist that can produce excitotoxic neuron damage. Type I and II interferons (IFNs) stimulate the KYN/TRP pathway, producing elevated QA/kynurenic acid (KA), a potential neurotoxic imbalance that may contribute to SLE-mediated cognitive dysfunction. We determined whether peripheral blood interferon-stimulated gene (ISG) expression associates with elevated serum KYN:TRP and QA:KA ratios in SLE.

Methods: ISG expression (whole-blood RNA sequencing) and serum metabolite ratios (high-performance liquid chromatography) were measured in 72 subjects with SLE and 73 healthy controls (HCs). ISG were identified from published gene sets and individual IFN scores were derived to analyse associations with metabolite ratios, clinical parameters and neuropsychological assessments. SLE analyses were grouped by level of ISG expression ('IFN high', 'IFN low' and 'IFN similar to HC') and level of monocyte-associated gene expression (using CIBERSORTx).

Results: Serum KYN:TRP and QA:KA ratios were higher in SLE than in HC (p<0.01). 933 genes were differentially expressed ≥2-fold in SLE versus HC (p<0.05). 70 of the top 100 most highly variant genes were ISG. Approximately half of overexpressed genes that correlated with KYN:TRP and QA:KA ratios (p<0.05) were ISG. In 36 IFN-high subjects with SLE, IFN scores correlated with KYN:TRP ratios (p<0.01), but not with QA:KA ratios. Of these 36 subjects, 23 had high monocyte-associated gene expression, and in this subgroup, the IFN scores correlated with both KY:NTRP and QA:KA ratios (p<0.05).

Conclusions: High ISG expression correlated with elevated KYN:TRP ratios in subjects with SLE, suggesting IFN-mediated KYN/TRP pathway activation, and with QA:KA ratios in a subset 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 patient subset may benefit from therapeutics directed at the IFN or KYN/TRP pathways to ameliorate a potentially neurotoxic QA/KA imbalance.

Keywords: Autoimmunity; Interferon Type I; Lupus Erythematosus, Systemic.

Figure 1

The kynurenine/tryptophan pathway. This is a simplified schematic of the KYN/TRP pathway, highlighting the intermediates and enzymes involved in the production of QA and KA. The enzyme IDO1 is stimulated by inflammatory cytokines, such as IFN, that results in the breakdown of TRP into KYN. KYN may be further metabolised by KMO ultimately to QA, an NMDAR agonist, or by KAT to KA, an NMDAR antagonist. Since the enzyme KMO has higher affinity for KYN than KAT, metabolism proceeds preferentially towards the production of QA in the setting of inflammation. IDO1, indolamine 2, 3-dioxygenase; IFN-α, interferon alpha; IFN-γ, interferon gamma; KA, kynurenic acid; KMO, kynurenine 3-monooxygenase; NMDAR, N-methyl-D-aspartate receptor; QA, quinolinic acid; TNF-α, tumour necrosis factor alpha.

Figure 2

Heat map of expression of 110 interferon-stimulated genes in SLE compared with HC. Subjects with SLE indicated by blue in the colour bar above the map, and HC indicated by red. ‘Pheatmap’ package V.1.0.12 is applied on DESeq2 normalised and variance stabilised gene expression values to create the heat map. HC, healthy control.

Figure 3

PCA of gene expression in SLE compared with HC. PCA conducted on DESeq2 normalised, and variance stabilised gene expression values, using the function prcomp in R V.3.5, is displayed. The default top 500 most highly variant genes were selected. HC, healthy control; PCA, principal component analysis.