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Oxidative stress and effector memory CD8+ T cells have been greatly implicated in vitiligo pathogenesis. However, the crosstalk between these two crucial pathogenic factors has been merely investigated. IL-15 has been regarded as an important cytokine exerting its facilitative effect on memory CD8+ T cells function in various autoimmune diseases. In the present study, we initially discovered that the IL-15 expression was significantly increased in vitiligo epidermis and highly associated with epidermal H 2 O 2 content. In addition, epidermal IL-15 expression was mainly derived from keratinocytes. Then, we showed that oxidative stress promoted IL-15 and IL-15Rα expression as well as IL-15 trans -presentation by activating NF-κB signaling in keratinocytes. What's more, the trans -presented IL-15, rather than the secreted one, was accounted for the potentiation of CD8+ T EMs activation. We further investigated the mechanism underlying trans -presented IL-15 in potentiating CD8+ T EMs activation and found that the blockage of IL-15-JAK-STAT signaling could be a potent therapeutic approach. Taken together, our results demonstrate that oxidative stress-induced IL-15 trans -presentation in keratinocytes contributes to the activation of CD8+ T EMs , providing a novel mechanism by which oxidative stress initiates autoimmunity in vitiligo. Image 1 • IL-15 links oxidative stress to immune response in vitiligo. • Oxidative stress increases IL-15 expression and trans -presentation in keratinocytes probably by NF-κB signaling. • Oxidative stress-induced IL-15 trans -presentation causes CD8+ T EMs activation via a cell-contact form in vitiligo. • Targeting the IL-15-JAK-STAT axis might shed new light on vitiligo treatment. [ABSTRACT FROM AUTHOR]

Abstract Vitiligo is a complex disorder characterized by patchy loss of skin pigmentation due to abnormal melanocyte function. Overwhelming evidences have suggested that oxidative stress plays a major role in the loss of melanocytes thereby mediating the onset and progression of vitiligo. The nuclear factor erythroid 2-like factor 2 (Nrf2) is a master regulator of cellular redox homeostasis and the activation of Nrf2 signaling pathway is impaired in the vitiligo melanocytes. Baicalein, as flavonoid extracted from the Scutellaria baicalensis , has been proved to possess the ability to activate Nrf2 signaling pathway in other cell types and mouse model. Our previous data found that baicalein exerts a cytoprotective role in H 2 O 2 -induced apoptosis in human melanocytes cell line (PIG1). Based on these founding, we hypothesized that baicalein activates Nrf2 signaling pathway, alleviates H 2 O 2 -induced mitochondrial dysfunction and cellular damage, thereby protecting human vitiligo melanocytes from oxidative stress. In the present study, we found that baicalein effectively inhibited H 2 O 2 -induced cytotoxicity and apoptosis in human vitiligo melanocytes (PIG3V). Further results demonstrated that baicalein promoted Nrf2 nucleus translocation as well as up-regulated the expression of Nrf2 and its target gene, heme oxygenase-1 (HO-1). Moreover, the protective effects of baicalein against H 2 O 2 -induced cellular damage and apoptosis as well as mitochondrial dysfunction were abolished by Nrf2 knockdown. Additionally, we observed that Nrf2 knockdown suppressed proliferation and increased the sensitivity of PIG3V cells to H 2 O 2 treatment. Finally, we explored the mechanism of baicalein associated with Nrf2 activation and found that the phosphorylation of Nrf2 as well as ERK1/2and PI3K/AKT signaling were not involved in the baicalein-induced activation of Nrf2. Taken together, these data clearly suggest that baicalein enhances cellular antioxidant defense capacity of human vitiligo melanocytes through the activation of the Nrf2 signaling pathway, providing beneficial evidence for the application of baicalein in the vitiligo treatment. Graphical abstract fx1 Highlights • Baicalein protects human vitiligo melanocytes against H 2 O 2 -induced oxidative stress. • The Nrf2/HO-1pathway is positively activated by baicalein during oxidative stress. • The protective effects of baicalein against oxidative stress are mediated by Nrf2. • Nrf2 knockdown suppresses the proliferation of human vitiligo melanocytes. • Nrf2 knockdown increases the sensitivity of human vitiligo melanocytes to H 2 O 2. [ABSTRACT FROM AUTHOR]