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 akeyrolein the induction and progression of psoriasis; thus, 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]. It has been proposed that shared inflammatory pathways may act as a driving force for both psoriasis and extracutaneous manifestations. Thus, a paradigm shift in concept of the pathophysiology of psoriasis has occurred; psoriasis is now viewed as a systemic inflammatory condition and not merely a “skin-deep” condition [4].

Tryptophan (TRP) metabolism pathway is strongly associated with immune suppression [5–7]. 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)1, or IDO2 (Figure 1). TDO is almost exclusively expressed in the liver and is induced in some cell types such as leukocytes and endothelial cells by TRP levels or corticosteroids [8]. IDO1 is the predominant enzyme extra-hepatically and is expressed in a lot of cell types including macrophages and keratinocytes [5, 6, 9, 10]. IDO1 is induced by various inflammatory cytokines such as interferon (IFN)-γ, and is upregulated in several inflammatory conditions including psoriasis [5, 11]. 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].

Kynureninase is an enzyme in the TRP-KYN metabolism pathway that metabolizes the KYN and 3-hydroxykynurenine (3HK) into anthranilic acid (AA) and 3-hydroxyanthranilic acid (3HAA), respectively. Among several key genes elucidated by microarray and genomic studies [13], kynureninase is one gene prominently upregulated in psoriasis [14–18]. It is highly upregulated in involved psoriatic skin compared to uninvolved skin, though which is still upregulated compared to the normal skin [5].

The TRP-KYN metabolism pathway [19] produces various metabolites, such as KYN, 3HK, kynurenic acid (KYNA), 3HAA, AA, and quinolinic acid (QA) (Figure 1). In the present study, the serum profiles of TRP-KYN pathway metabolites were comprehensively examined in psoriatic patients (PSOs) to verify the involvement of this pathway in the pathophysiology of psoriasis and to evaluate the serum profiles of new psoriasis-related biomarkers that reflect systemic inflammation in PSOs. In addition, we aimed to assess the ratios of TRP-KYN pathway metabolites as indices of two main enzymes, IDO1 and kynureninase, in this pathway.

In the present study, the serum profiles of TRP-KYN pathway metabolites and the ratios of the metabolites were comprehensively evaluated in the PSOs. Consequently, the serum TRP, KYN, and KYNA concentrations were significantly lower, but the 3HAA concentrations were markedly higher in PSOs than in the HCs (Table 1). The ratios of 3HAA to 3HK, 3HK to KYN, and 3HAA to AA were significantly increased (Table 2). The TRP, KYNA, and 3HK levels were weakly negatively correlated with the PASI scores (Table 3). These results indicate that the TRP-KYN-3HK-3HAA metabolic pathway is upregulated in psoriasis. The concentrations of KYNA, which is present downstream of KYN, may be reduced following the decreased KYN concentrations. Although AA is also present downstream of KYN, the pathway from KYN to AA by kynureninase may be enhanced in the PSOs, resulting in no differences of AA levels between the PSOs and HCs.

IDO1 and kynureninase have been reported as two main enzymes in TRP-KYN pathway. IDO1 and kynureninase are upregulated in the involved skin, compared to the uninvolved skin of PSOs [5, 11, 21, 22]. IDO1 acts as an immune modulator in immune cells of healthy conditions [23]. KYNA [24] and KYN generated by IDO1 exert active immune-suppressive effects [7], through mechanisms such as inducing regulatory T cells via binding to the aryl-hydrocarbon receptor (AhR) [25, 26]. There have not been fully studied about IDO2 and TDO in psoriasis. IDO2 decreases IL-17 expression, resulting in the suppression of skin inflammation in imiquimod-induced psoriasis-like dermatitis [27]. In the present study, the TRP levels decreased in the PSOs, suggesting IDO1 activation. However, the KYN levels also decreased and the KYN/TRP ratio did not show the differences between the PSOs and HCs. These data may suggest activation of kynureninase and/or kynurenine 3-monooxygenase (KMO). As successful treatments to psoriasis reduce IDO1 and kynureninase [5], KYN/TRP ratio might be affected by various treatments in the present study. Otherwise, the activities of TDO or IDO2 might be involved in the KYN generation in psoriasis.

The AA/KYN and 3HAA/3HK ratios were assessed as possible indices of kynureninase. The AA/KYN ratio and AA concentrations did not show a difference between the PSOs and HCs, but were positively correlated with PASI scores (Table 3), suggesting that the pathway from KYN to AA may be enhanced strongly in the PSOs with higher PASI scores, but not in those with lower PASI scores. The 3HAA/3HK ratio was significantly elevated in the PSOs than HCs, but was not correlated with PASI scores. It suggests that the pathway from 3HK to 3HAA, which is main reaction by kynureninase, is fully activated in the PSOs independently of PASI scores. As human kynureniase prefers 3HK to KYN as a substrate, the reaction rate may not be the same between KYN to AA and 3HK to 3HAA.

From these results, it is suggested that kynureninase activity is upregulated in PSOs. Therefore, the enhanced expression of kynureninase was confirmed histologically in the epidermis from psoriatic skin, both the involved and uninvolved skin, compared to the healthy skin (Figure 2). However, unfortunately, the kynureninase activity could not be determined in the psoriatic skin in this study.

The 3HAA/AA ratio has been reported to show possibly an inflammatory state, with a decrease indicating an anti-inflammatory response [28, 29]. In the present study, the 3HAA/AA ratio was significantly higher in the PSOs than in HCs, and was weakly negatively correlated with PASI scores. Not only kynureninase but also the other enzymes such as KMO are involved in this metabolic pathway, and thus the activity of KMO might be altered in the PSOs.

Several studies have determined the serum levels of cytokines and chemokines in PSOs, but the results are controversial [30, 31]. It can be said that the correlation between the levels of TRP-KYN pathway metabolites and cytokines has not been fully understood. KYNA plays an important role in modulating the expression of IL-23 and IL-17 in dendritic cells and T helper 17 (Th17) cells [32]. The interaction between AhR and endogenous ligands such as KYN and KYNA is known to alter the inflammatory profiles of psoriasis [33]. Altered regulation of TRP-KYN metabolism may reduce the levels of AhR ligands [24, 34], resulting in the increased expression of proinflammatory cytokines in psoriatic lesions [35]. Although increased IP-10 expression has been reported in the epidermis of psoriasis [36, 37], the serum IP-10 levels were significantly lower in PSOs than in HCs (Table 4) and were positively correlated with the AA, KYN, and KYNA levels (Table 5). It is suggested that some cytokines and chemokines including IP-10 play a role in the pathogenesis of psoriasis in association with TRP-KYN metabolism pathway. However, as the treatment for psoriasis varies in the present study, the correlation between cytokine levels and TRP-KYN pathway metabolites may be affected by the treatments.

TRP-KYN pathway metabolites present downstream of kynureninase upregulate several cytokines, chemokines, and cell adhesions-related factors. Of interest is that the dichotomous actions of TRP metabolism have been described in neurobiology, with early TRP metabolites such as KYN being considered to possess a neuroprotective role and late TRP metabolites, such as QA, demonstrating neurotoxic activity [38, 39]. Future studies that examine all the enzymes within this pathway will provide a clue to understand how this pathway is involved in the inflammation. In addition, the relationship between TRP-KYN metabolism and the immune system may be more complicated and remains to be ascertained in further studies. In addition, TRP metabolism is reported to modulate immune responses dichotomously with kynureninase as a switch between immunosuppressive and inflammatory outcomes, in not only psoriasis, but in other inflammatory diseases [5].

In conclusion, the serum profiles of TRP-KYN pathway metabolites differed between PSOs and HCs, suggesting that kynureninase activity is upregulated in PSOs compared to that in HCs. Limitations of our study are the small sample size and variety of treatments; hence, further studies are required to completely assess the involvement of TRP-KYN pathway metabolites in the pathogenesis of psoriasis and the outcome may give us the potential of these metabolites to serve as biomarkers for psoriasis.