Abstract
Aim: Chronic inflammation is closely associated with tryptophan (TRP)-kynurenine (KYN) metabolic pathway. However, TRP-KYN pathway has not been fully elucidated in psoriasis, a systemic inflammatory disease with skin lesions and extracutaneous manifestations. Herein, we studied comprehensively serum profiles of TRP-KYN pathway metabolites in psoriatic patients (PSOs) to clarify the involvement of this pathway in the pathophysiology of psoriasis and to evaluate serum biomarkers reflecting systemic inflammation in PSOs. Methods: The concentrations of main TRP metabolites, TRP, KYN, 3-hydroxykynurenine (3HK), kynurenic acid (KYNA), 3-hydroxyanthranilic acid (3HAA), and anthranilic acid (AA), were determined by high-performance liquid chromatography in the sera from 65 PSOs and 35 healthy controls (HCs). The levels of these metabolites and the ratios of metabolites were compared between these subjects. The correlations between these values and the psoriasis area severity index (PASI) scores were analyzed. Skin samples from PSOs and HCs were subjected to immunohistochemical staining for kynureninase. Cytokine concentrations were comprehensively measured in the same samples and the correlations between the cytokine levels and TRP-KYN pathway metabolite levels were examined. Results: Serum TRP, KYN, and KYNA concentrations were lower and the 3HAA concentrations were higher in PSOs than in HCs. The ratios of 3HK/KYN, 3HAA/3HK, and 3HK/AA were higher in PSOs than in HCs. The AA levels and the ratio of AA/KYN were weakly positively correlated, and TRP, KYNA, and 3HK levels and the ratios of KYNA/KYN and 3HAA/AA were weakly negatively correlated with the PASI scores. The AA, KYN, and KYNA levels were positively correlated with the interferon gamma-induced protein 10 (IP-10) concentrations. Kynureninase expression was enhanced in the epidermis, both involved and uninvolved skin. Conclusions: Serum profiles of TRP-KYN pathway metabolites differed between PSOs and HCs. TRP-KYN pathway-associated processes, including kynureninase activation, may be involved in the pathogenesis of psoriasis, and thus serve as targets for psoriasis therapy.
Highlights
Psoriasis is a chronic inflammatory skin disease characterized by the thickening of the epidermis and skin infiltration of polymorphonuclear cells
Serum TRP, KYN, and kynurenic acid (KYNA) concentrations were lower and the 3-hydroxyanthranilic acid (3HAA) concentrations were higher in PSOs than in healthy controls (HCs)
The anthranilic acid (AA) levels and the ratio of AA/KYN were weakly positively correlated, and TRP, KYNA, and 3HK levels and the ratios of KYNA/KYN and 3HAA/AA were weakly negatively correlated with the psoriasis area severity index (PASI) scores
Summary
Psoriasis is a chronic inflammatory skin disease characterized by the thickening of the epidermis and skin infiltration of polymorphonuclear cells. The tumor necrosis factor (TNF)-α/interleukin (IL)-23/IL-17A axis plays a key role in the induction and progression of psoriasis; biological drugs against TNF-α/IL-23/IL-17A show a good therapeutic efficacy [1, 2]. Various comorbidities such as cardiovascular disease, metabolic syndrome, inflammatory bowel disease, and depression are associated with psoriasis [3]. TRP is oxidized by cleavage of the indole ring moiety, and kynurenine (KYN) is generated. This pathway is initiated either by tryptophan 2,3-dioxagenase (TDO), indoleamine 2,3-dioxygenase (IDO), or IDO2 (Figure 1). IDO2, an isotype enzyme of IDO1, shows similar structural and enzymatic activities as IDO1, but differs in its expression pattern, substrate specificity, and downstream signaling pathways [12]
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