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

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.