Kynureninase contributes to the pathogenesis of psoriasis through pro‐inflammatory effect

• Published in: Journal of cellular physiology 2022-01, Vol.237 (1), p.1044-1056
• Main Authors: Wang, Min, Wang, Yuqian, Zhang, Mengdi, Duan, Qiqi, Chen, Caifeng, Sun, Qiong, Liu, Meng, Zheng, Yan, Shao, Yongping
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Cell lines; Cell Proliferation - genetics; Cytokines; Enzymes; Humans; Hydrolases; Imiquimod - adverse effects; Immunohistochemistry; Inflammation; Inflammation - metabolism; inhibitor; Keratinocytes; Keratinocytes - metabolism; KYNU; Mice; MicroRNAs; MicroRNAs - metabolism; miRNA; miR‐203a; Pathogenesis; Phenotypes; Polymerase chain reaction; Psoriasis; Psoriasis - chemically induced; Psoriasis - drug therapy; Psoriasis - genetics; Ribonucleic acid; RNA; Skin; Skin - metabolism; Skin diseases; Therapeutic targets; Tryptophan
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.30587

Kynureninase (KYNU) is a key enzyme in the tryptophan metabolism pathway with elevated expression in psoriatic lesions relative to normal skin. However, whether KYNU contributes to the pathogenesis of psoriasis remains unknown. We sought to investigate the role of KYNU in psoriasis and its possible regulation mechanism. In the results, KYNU is upregulated in psoriatic skin samples from patients or animal models compared with normal skin control which was assayed in psoriatic patient samples, IMQ‐induced psoriasis‐like skin inflammation in BABL/c mice and M5‐stimulated keratinocyte cell lines by immunohistochemistry (IHC). KYNU knockdown had a trivial impact on keratinocyte proliferation, but significantly inhibited the production of inflammatory cytokines in HaCaT, HEKα, and HEKn cells by quantitative reverse‐transcription polymerase chain reaction, enzyme‐linked immunosorbent assay, and western blot analysis. The 3ʹ‐untranslated region of KYNU contains a conserved target site of a skin‐specific microRNA (miRNA), miR‐203a, as predicted by TargetScan software. Furthermore, miR‐203a exhibited an inversed expression kinetics to KYNU during the development of IMQ‐induced psoriasis‐like skin inflammation in BABL/c mice. Overexpression of miR‐203 subsequently leading to the inhibition of KYNU, could significantly reduce the production of M5‐induced, psoriasis‐related inflammatory factors in keratinocytes. Finally, KYNU inhibitors could alleviate the pathological phenotypes in IMQ‐mice. Our study supported the contributive role of KYNU in the development of psoriasis and provided preliminary evidence for KYNU as a potential therapeutic target in psoriasis. This study revealed a proinflammation role of kynureninase (KYNU) in keratinocytes, depicted a miR‐203a/KYNU/inflammation axis that may contribute to the development of psoriasis and provided a rationale for utilizing KYNU as a therapeutic target of psoriasis.