Juvenile Arthritis Patients Suffering from Chronic Inflammation Have Increased Activity of Both IDO and GTP-CH1 Pathways But Decreased BH4 Efficacy: Implications for Well-Being, Including Fatigue, Cognitive Impairment, Anxiety, and Depression

Abstract

Juvenile idiopathic arthritis (JIA) represents joint inflammation with an unknown cause that starts before the age of 16, resulting in stiff and painful joints. In addition, JIA patients often report symptoms of sickness behavior. Recent animal studies suggest that proinflammatory cytokines produce sickness behavior by increasing the activity of indoleamine-2,3-dioxygenase (IDO) and guanosinetriphosphate–cyclohydrolase-1 (GTP–CH1). Here, it is hypothesized that inflammation in JIA patients enhances the enzymatic activity of IDO and GTP-CH1 and decreases the co-factor tetrahydrobiopterin (BH4). These compounds play a crucial role in the synthesis and metabolism of neurotransmitters. The aim of our study was to reveal whether inflammation affects both the GTP-CH1 and IDO pathway in JIA patients. Serum samples were collected from twenty-four JIA patients. In these samples, the concentrations of tryptophan (TRP), kynurenine (KYN), tyrosine (TYR), neopterin, and phenylalanine (PHE) were measured. An HPLC method with electrochemical detection was developed to quantify tryptophan, kynurenine, and tyrosine. Neopterin and phenylalanine were quantified by ELISA. The KYN/TRP ratio was measured as an index of IDO activity, while the PHE/TYR ratio was measured as an index of BH4 activity. Neopterin concentrations were used as an indirect measure of GTP-CH1 activity. JIA patients with high disease activity showed higher levels of both neopterin and kynurenine, and a higher ratio of both KYN/TRP and PHE/TYR and lower tryptophan levels than clinically inactive patients. Altogether, these data support our hypothesis that inflammation increases the enzymatic activity of both IDO and GTP-CH1 but decreases the efficacy of the co-factor BH4. In the future, animal studies are needed to investigate whether inflammation-induced changes in these enzymatic pathways and co-factor BH4 lower the levels of the brain neurotransmitters glutamate, noradrenaline, dopamine, serotonin, and melatonin, and consequently, whether they may affect fatigue, cognition, anxiety, and depression. Understanding of these complex neuroimmune interactions provides new possibilities for Pharma-Food interventions to improve the quality of life of patients suffering from chronic inflammation.

Cross-Tissue Transcriptomic Analysis Leveraging Machine Learning Approaches Identifies New Biomarkers for Rheumatoid Arthritis

“…Some genes/proteins, e.g. S100A8/MRP8, ENTPD1/CD39, KYNU, and TNFAIP6, from the score were previously found to be associated with JIA (Bojko, 2017; Brachat et al, 2017; Griffin et al, 2009; Hinze et al, 2019; Holzinger et al, 2019; Jiang et al, 2013; Korte-Bouws et al, 2019; Moncrieffe et al, 2010). Treatment effect was also captured with a significantly lower RA Score for DMARD-treated patients compared to untreated patients.…”

Phenylketonuria and juvenile idiopathic arthritis: a case report

“…The accumulation of some abnormal metabolites like glycosaminoglycans, adiponectin and leptin may be involved in the development and progression of joint dysfunction in JIA [ 4 ]. A recent metabolomics analysis revealed significantly higher ratios of both kynurenine/ tryptophan and phe/tyr and lower tryptophan levels in serum sample of JIA patients with high disease activity than those of clinically inactive patients [ 5 ]. The researches proposed a hypothesis that chronic inflammation could alter tryptophan and tyrosine metabolism [ 6 ].…”

Fatigue in inflammatory rheumatic disorders: pathophysiological mechanisms

“…3) [164]. This can affect neurotransmitter concentrations of serotonin, dopamine and noradrenaline and increased levels of glutamate and quinolinic acid (NMDA-receptor agonist) (Figs 3 and 4) [164]. Similar changes in activity of IDO and GTP-CH1 pathways have been observed in low-grade inflammation in the elderly that was associated with general fatigue and reduced motivation, sleep alterations, reduced appetite and digestive symptoms [165].…”

“…In children with juvenile arthritis suffering from chronic inflammation and fatigue, an increased activity of both IDO and GTP-CH1 pathways and a decreased BH4 efficacy were observed (see also Fig. 3) [164]. This can affect neurotransmitter concentrations of serotonin, dopamine and noradrenaline and increased levels of glutamate and quinolinic acid (NMDA-receptor agonist) (Figs 3 and 4) [164].…”