Alteration in kynurenine pathway metabolites in young women with autoimmune thyroiditis

Abstract

The kynurenine pathway (KP) of tryptophan degradation includes several compounds that reveal immunomodulatory properties. The present study aimed to investigate the alteration in KP metabolites in young women with autoimmune thyroiditis (AIT) and their associations with thyroid function. The thyroid function tests, antithyroid antibodies measurement and ultrasonography of the thyroid gland have been performed in 57 young women with AIT and 38 age-matched healthy controls. The serum levels of tryptophan, kynurenine (KYN) and its metabolites were determined, and the activity of KP enzymes was calculated indirectly as product-to-substrate ratios. KP was activated and dysregulated in AIT, along with significantly elevated levels of KYN and anthranilic acid (AA), at the expense of the reduction of kynurenic acid (KYNA), which was reflected by the increase in the AA/KYNA ratio (p < 0.001). In univariate and multiple regression analyses, peripheral deiodinase (SPINA-GD) activity in AIT was positively associated with KYNA, AA, and quinolinic acid (QA). The merger of AA, AA/KYNA ratio, QA and SPINA-GD exhibited the highest sensitivity and specificity to predict AIT (p < 0.001) in receiver operating characteristic (ROC) analysis. In conclusion, the serum KYN metabolite profile is dysregulated in young women with AIT and could serve as a new predictor of AIT risk.

Genetically predicted metabolites mediate the causal associations between autoimmune thyroiditis and immune cells

“…Upon immune stimulation, the so called ‘kynurenine switch’ snaps into action, and most Trp molecules enter immunocompetent cells and are metabolized therein via the kynurenine pathway ( 47 ). Kynurenine binds to the aryl hydrocarbon receptor (AHR) in multiple immune cell types, leading to immune regulation ( 19 , 48 ). It has been shown that after immune stimulation, immune cells generate high levels of various intracellular Trp metabolites ( 49 ), which in turn is involved in the induction of the synthesis of cytoskeletal proteins and regulation of immune cell motility ( 50 ).…”

“…It has been shown that after immune stimulation, immune cells generate high levels of various intracellular Trp metabolites ( 49 ), which in turn is involved in the induction of the synthesis of cytoskeletal proteins and regulation of immune cell motility ( 50 ). Indoleamine 2,3-dioxygenase 1 (IDO1), the key enzyme of kynurenine pathway, is one of the major regulators of the function of immune cells, controlling the balance between stimulation and suppression of the immune system at sites of local inflammation and thus is relevant to a wide range of autoimmune and inflammatory diseases ( 19 ). Significant attention has been paid to the immunoregulatory role of IDO1 in the most prevalent, organ-specific autoimmune endocrinopathies such as T1D and AIT ( 19 , 48 ).…”

“…Indoleamine 2,3-dioxygenase 1 (IDO1), the key enzyme of kynurenine pathway, is one of the major regulators of the function of immune cells, controlling the balance between stimulation and suppression of the immune system at sites of local inflammation and thus is relevant to a wide range of autoimmune and inflammatory diseases ( 19 ). Significant attention has been paid to the immunoregulatory role of IDO1 in the most prevalent, organ-specific autoimmune endocrinopathies such as T1D and AIT ( 19 , 48 ). It was reported that the serum kynurenine metabolite profile was dysregulated in young women with AIT and could serve as a new predictor of AIT risk ( 19 ).…”

“…Significant attention has been paid to the immunoregulatory role of IDO1 in the most prevalent, organ-specific autoimmune endocrinopathies such as T1D and AIT ( 19 , 48 ). It was reported that the serum kynurenine metabolite profile was dysregulated in young women with AIT and could serve as a new predictor of AIT risk ( 19 ). Numerous studies have been devoted to the role of metabolites of the kynurenine pathway of Trp metabolism in immune regulation, as well as to the analysis of the effects of kynurenine on the activity of immunocompetent cells ( 48 ).…”

“…Krupa et al. reported that the serum kynurenine metabolite profile was dysregulated in young women with AIT and could serve as a new predictor of AIT risk ( 19 ). Song et al.…”