Wang Min, Wang Yuqian, Zhang Mengdi, Duan Qiqi, Chen Caifeng, Sun Qiong, Liu Meng, Zheng Yan, Shao Yongping
Department of Dermatology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
Department of Dermatology, Fujian Provincial Hospital, Clinical Medical College, Fujian Medical University, Fuzhou, China.
J Cell Physiol. 2022 Jan;237(1):1044-1056. doi: 10.1002/jcp.30587. Epub 2021 Sep 22.
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 3'-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.
犬尿氨酸酶（KYNU）是色氨酸代谢途径中的关键酶，相对于正常皮肤，其在银屑病皮损中的表达升高。然而，KYNU是否促成银屑病的发病机制仍不清楚。我们试图研究KYNU在银屑病中的作用及其可能的调控机制。结果显示，通过免疫组织化学（IHC）检测，与正常皮肤对照相比，来自患者或动物模型的银屑病皮肤样本中KYNU上调，该对照在银屑病患者样本、IMQ诱导的BABL/c小鼠银屑病样皮肤炎症以及M5刺激的角质形成细胞系中进行检测。通过定量逆转录聚合酶链反应、酶联免疫吸附测定和蛋白质印迹分析，敲低KYNU对角质形成细胞增殖影响不大，但显著抑制了HaCaT、HEKα和HEKn细胞中炎性细胞因子的产生。如TargetScan软件预测的那样，KYNU的3'-非翻译区包含皮肤特异性微小RNA（miRNA）miR-203a的保守靶位点。此外，在BABL/c小鼠IMQ诱导的银屑病样皮肤炎症发展过程中，miR-203a表现出与KYNU相反的表达动力学。随后，miR-203的过表达导致KYNU受到抑制，可显著减少角质形成细胞中M5诱导的、与银屑病相关的炎性因子的产生。最后，KYNU抑制剂可减轻IMQ小鼠的病理表型。我们的研究支持了KYNU在银屑病发展中的作用，并为KYNU作为银屑病潜在治疗靶点提供了初步证据。
