Cao Cheng, Xu Wen, Lei Jingdi, Zheng Yujie, Zhang An, Xu Aie, Lin Fuquan, Zhou Miaoni
Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China.
School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
Inflamm Res. 2025 Apr 29;74(1):72. doi: 10.1007/s00011-025-02035-2.
Psychological stress is the most common psychological comorbidity and a significant triggering factor of vitiligo. Moderate to severe psychological stress can markedly affect the efficacy of vitiligo treatment. However, the specific mechanisms underlying its involvement remain insufficiently studied.
Chronic unpredictable mild stress (CUMS)-induced major depressive disorder (MDD)-like behavior was modeled in C57BL/6 mice alongside wild-type mice to investigate differences in vitiligo pathogenesis. White spot tissues from mouse tails were subjected to high-throughput transcriptomic sequencing (RNA-seq). In vitro experiments utilized β-galactosidase, P16, and P21 to assess IFN-γ-induced senescence. The effects of exogenous IL-6 on fibroblast senescence were assessed, and the role of blocking the IL-6 autocrine loop with an IL-6R inhibitor in reversing IFN-γ-induced fibroblast senescence was evaluated.
CUMS-induced MDD -like mice exhibited significantly lower body mass index and sugar-water preference index compared to wild-type mice, and their vitiligo severity was markedly increased. Transcriptomic sequencing revealed significant upregulation of cellular senescence and JAK-STAT signaling pathways in white spot tissues of depressive-like vitiligo mice. In vitro findings indicated that IFN-γ induced fibroblast senescence via activation of the JAK2-STAT3 signaling pathway, which subsequently promoted melanocyte apoptosis and increased IL-6 secretion and IL-6R expression. Exogenous IL-6 further activated the JAK2-STAT3 signaling pathway, induced fibroblast senescence, and synergistically intensified IFN-γ-induced fibroblast senescence.
Excessive activation of the IL-6 autocrine loop, synergizing with IFN-γ to aggravate fibroblast senescence and promote melanocyte apoptosis. Blocking the IL-6 autocrine loop may serve as an effective approach to mitigate the impact of CUMS on vitiligo pathogenesis and treatment efficacy.
心理应激是白癜风最常见的心理合并症和重要触发因素。中度至重度心理应激可显著影响白癜风治疗效果。然而，其具体作用机制仍研究不足。
在C57BL/6小鼠及野生型小鼠中建立慢性不可预测轻度应激（CUMS）诱导的重度抑郁症（MDD）样行为模型，以研究白癜风发病机制的差异。对小鼠尾部白斑组织进行高通量转录组测序（RNA-seq）。体外实验利用β-半乳糖苷酶、P16和P21评估IFN-γ诱导的衰老。评估外源性IL-6对成纤维细胞衰老的影响，并评价用IL-6R抑制剂阻断IL-6自分泌环在逆转IFN-γ诱导的成纤维细胞衰老中的作用。
与野生型小鼠相比，CUMS诱导的MDD样小鼠体重指数和糖水偏好指数显著降低，白癜风严重程度明显增加。转录组测序显示，抑郁样白癜风小鼠白斑组织中细胞衰老和JAK-STAT信号通路显著上调。体外研究结果表明，IFN-γ通过激活JAK2-STAT3信号通路诱导成纤维细胞衰老，随后促进黑素细胞凋亡，并增加IL-6分泌和IL-6R表达。外源性IL-6进一步激活JAK2-STAT3信号通路，诱导成纤维细胞衰老，并协同增强IFN-γ诱导的成纤维细胞衰老。
IL-6自分泌环过度激活，与IFN-γ协同作用加重成纤维细胞衰老，促进黑素细胞凋亡。阻断IL-6自分泌环可能是减轻CUMS对白癜风发病机制和治疗效果影响的有效方法。
