背景:在白癜风中观察到色氨酸代谢失调。然而,在这种代谢紊乱和白癜风发病机制之间建立机制联系仍然具有挑战性.
目的:旨在揭示白癜风中色氨酸代谢的特点,探讨色氨酸代谢产物在白癜风病理生理中的作用。
方法:LC-MS/MS,双荧光素酶报告分析,ELISA,qRT-PCR,小干扰RNA,西方印迹,采用免疫组织化学。
结果:确定了稳定的非节段白癜风血浆中犬尿氨酸通路的激活和与犬尿氨酸(KYNA)的KYAT酶相关偏差。使用公共微阵列数据集,我们进一步验证犬尿氨酸通路的激活与白癜风患者皮肤炎症相关基因的表达有关。此外,我们发现KYNA通过AhR激活诱导角质形成细胞中CXCL10的上调。此外,白癜风患者血浆中AhR激动剂的总活性增加,而AhR浓度本身降低。最后,更高的KYAT,免疫组织化学染色观察白癜风皮损中CXCL10,CYP1A1和较低的AhR表达。
结论:这项研究描述了白癜风中色氨酸代谢的代谢和遗传特征,并提出KYNA,色氨酸衍生的AhR配体,可以增强CXCL10在角质形成细胞中的表达。
BACKGROUND: Tryptophan metabolism dysregulation has been observed in vitiligo. However, drawing a mechanistic linkage between this metabolic disturbance and vitiligo pathogenesis remains challenging.
OBJECTIVE: Aim to reveal the characterization of tryptophan metabolism in vitiligo and investigate the role of tryptophan metabolites in vitiligo pathophysiology.
METHODS: LC-MS/MS, dual-luciferase reporter assay, ELISA, qRT-PCR, small interfering RNA, western blotting, and immunohistochemistry were employed.
RESULTS: Kynurenine pathway activation and KYAT enzyme-associated deviation to kynurenic acid (KYNA) in the plasma of stable non-segmental vitiligo were determined. Using a public microarray dataset, we next validated the activation of kynurenine pathway was related with inflammatory-related genes expression in skin of vitiligo patients. Furthermore, we found that KYNA induced CXCL10 upregulation in keratinocytes via AhR activation. Moreover, the total activity of AhR agonist was increased while the AhR concentration per se was decreased in the plasma of vitiligo patients. Finally, higher KYAT, CXCL10, CYP1A1 and lower AhR expression in vitiligo lesional skin were observed by immunohistochemistry staining.
CONCLUSIONS: This study depicts the metabolic and genetic characterizations of tryptophan metabolism in vitiligo and proposes that KYNA, a tryptophan-derived AhR ligand, can enhance CXCL10 expression in keratinocytes.