Enhanced tryptophan-kynurenine metabolism via indoleamine 2,3-dioxygenase 1 induction in dermatomyositis

Abstract

Objectives Extrahepatic tryptophan (Trp)-kynurenine (Kyn) metabolism via indoleamine 2,3-dioxygenase 1 (IDO1) induction was found to be associated with intrinsic immune regulation. However, the Trp-Kyn metabolism–associated immune regulation in dermatomyositis (DM) remains unknown. Therefore, we aimed to investigate the clinical relevance of the Trp-Kyn metabolism via IDO1 induction in DM. Methods Liquid chromatography-mass spectrometry (HPLC–MS) was used to examine the serum Kyn and Trp concentrations in DM. In addition, we used X-tile software to determine the optimal cutoff value of the Kyn/Trp ratio, a surrogate marker for Trp-Kyn metabolism. Spearman analysis was performed to evaluate the association of Trp-Kyn metabolism with muscle enzymes and inflammatory markers. Results DM patients had significantly higher serum Kyn/Trp ratio (× 10−3) when compared with the healthy controls. The serum Kyn/Trp ratio was positively correlated with the levels of muscle enzymes and inflammatory markers. In addition, the serum Kyn/Trp ratio significantly decreased (36.89 (26.00–54.00) vs. 25.00 (18.00–37.00), P = 0.0006) after treatment. DM patients with high serum Kyn/Trp ratio had a significantly higher percentage of muscle weakness symptoms (62.5% vs. 20.0%, P = 0.019) and higher levels of LDH (316.0 (236.0–467.0) vs. 198.0 (144.0–256.0), P = 0.004) and AST (56.5 (35.0–92.2) vs. 23.0 (20.0–36.0), P = 0.002)) than those with low serum Kyn/Trp ratio. Multiple Cox regression analyses identified ln(Kyn/Trp) (HR 4.874, 95% CI 1.105–21.499, P = 0.036) as an independent prognostic predictor of mortality in DM. Conclusions DM patients with enhanced Trp-Kyn metabolism at disease onset are characterized by more severe disease status and poor prognosis. Intrinsic immune regulation function via enhanced Trp-Kyn metabolism by IDO1 induction may be a potential therapeutic target in DM. Key Points• HPLC–MS identified increased serum Kyn/Trp ratio in DM patients, which positively correlated with levels of muscle enzymes and inflammatory markers and was downregulated upon treatment.• More attention to psychological status is needed in RA patients.• Cox regression analyses identified ln(Kyn/Trp) as an independent prognostic predictor of mortality in DM.

Normative Data on Serum and Plasma Tryptophan and Kynurenine Concentrations from 8089 Individuals Across 120 Studies: A Systematic Review and Meta-Analysis

“… 160 The studies which were appraised to be of low quality often reported significant deviations from the calculated grand population mean. 43 , 60 , 69 , 84 , 130 Nonetheless, this meta-analysis featured a very large sample size and TRP and KYN means are generally considered statistically reliable.…”

“…160 The studies which were appraised to be of low quality often reported significant deviations from the International Journal of Tryptophan Research calculated grand population mean. 43,60,69,84,130 Nonetheless, this meta-analysis featured a very large sample size and TRP and KYN means are generally considered statistically reliable. TRP and KYN concentrations were lower in female than male participants across both serum and plasma, an observation typically observed in younger healthy cohorts.…”