2. Academic Validation
  3. The IL-6 autocrine loop promoting IFN-γ-induced fibroblast senescence is involved in psychological stress-mediated exacerbation of vitiligo

The IL-6 autocrine loop promoting IFN-γ-induced fibroblast senescence is involved in psychological stress-mediated exacerbation of vitiligo

  • Inflamm Res. 2025 Apr 29;74(1):72. doi: 10.1007/s00011-025-02035-2.
Cheng Cao # 1 2,  Wen Xu # 1 3,  Jingdi Lei 1 2,  Yujie Zheng 1 2,  An Zhang 1 2,  Aie Xu 1 3,  Fuquan Lin 4 5,  Miaoni Zhou 6 7
Affiliations

Affiliations

  • 1 Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China.
  • 2 School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
  • 3 Department of Dermatology, Hangzhou Third People's Hospital, 38 Xihu Rd, Hangzhou, 310009, Zhejiang, China.
  • 4 Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China. fuquanlin528@sina.com.
  • 5 Department of Dermatology, Hangzhou Third People's Hospital, 38 Xihu Rd, Hangzhou, 310009, Zhejiang, China. fuquanlin528@sina.com.
  • 6 Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China. zhoumiaoni@163.com.
  • 7 Department of Dermatology, Hangzhou Third People's Hospital, 38 Xihu Rd, Hangzhou, 310009, Zhejiang, China. zhoumiaoni@163.com.
  • # Contributed equally.
PMID: 40299037 DOI: 10.1007/s00011-025-02035-2
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords

Cellular senescence; Chronic unpredictable mild stress (CUMS); Fibroblasts; IL-6; Vitiligo.

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