Abstract
Vitiligo is an acquired skin depigmentation disease in which excessive reactive oxygen species (ROS) play a critical pathogenic role in melanocyte destruction. The complex crosstalk between melanocytes and keratinocytes in vitiligo suggests that treatments aimed at protecting both the cells might be meaningful. In this study, we investigated the effect of 4-octyl itaconate (4-OI), an itaconate derivative, on ultraviolet B- (UVB-) induced apoptosis in HaCaT and PIG1 cells and the underlying mechanisms. HaCaT and PIG1 cells were pretreated with 4-OI (50 or 100 μM) for 24 h and then exposed to 300 mJ/cm2 UVB (emission range 290–320 nm, emission peak 310 nm). ROS levels and cell apoptosis were investigated using fluorescence microscopy and flow cytometry 24 h after irradiation. In addition, nuclear translocation and the expression of pathway-related proteins and mRNAs were detected using confocal microscopy, western blotting, and qRT-PCR, respectively. Our results demonstrated that UVB induced apoptosis in HaCaT and PIG1 cells, whereas inhibition of ROS production could reverse this effect. Furthermore, 4-OI attenuated UVB-induced apoptosis in HaCaT and PIG1 cells in a concentration-dependent manner by reducing the ROS levels. Moreover, 4-OI induced nuclear translocation and activation of nuclear factor erythroid 2-related factor 2 (Nrf2), and Nrf2 silencing reversed the inhibitory effect of 4-OI on the UVB-induced increase in ROS production and apoptosis in HaCaT and PIG1 cells. In addition, in vivo experiments using the Institute of Cancer Research mouse model showed that 4-OI via tail vein injection (10 mg/kg/day for six consecutive days) could reduce skin damage induced by UVB (400 mJ/cm2/day for five consecutive days). In conclusion, 4-OI can protect melanocytes and keratinocytes from UVB-induced apoptosis by Nrf2 activation-dependent ROS inhibition and can potentially treat skin disorders associated with oxidative stress, such as vitiligo.
Highlights
Vitiligo is a chronic, acquired disorder characterized by skin depigmentation, with an estimated global prevalence of 0.5%–1.0% [1]
The results showed that 4-octyl itaconate (4-OI) reversed the ultraviolet B- (UVB-)induced inhibition of cell viability in a concentration-dependent manner in both cell lines (Figure 1(c))
We showed that pretreatment with 4-OI attenuated the morphological changes caused by ultraviolet B (UVB) irradiation in HaCaT and PIG1 cells (Figure 1(d))
Summary
Vitiligo is a chronic, acquired disorder characterized by skin depigmentation, with an estimated global prevalence of 0.5%–1.0% [1]. Several factors such as environmental stimuli, gene susceptibility, autoimmune dysregulation, and oxidative stress are associated with vitiligo development [2, 3]. It is widely accepted that ultraviolet B (UVB) irradiation (290–320 nm) can lead to excessive reactive oxygen species (ROS) production and cell apoptosis and may trigger vitiligo flare-up [2, 8, 9]. Aberrant ROS generation caused by UVB irradiation can lead to melanocyte stress, promote protein oxidation and carbonylation, and result in melanocyte dysfunction [10]. Growing evidence suggests a complex link between keratinocytes and melanocytes under oxidative stress conditions. A study reported that keratinocytes released extracellular adenosine 5′-triphosphate (ATP) after oxidative
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