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Four-Octyl Itaconate Attenuates UVB-Induced Melanocytes and Keratinocytes Apoptosis by Nrf2 Activation-Dependent ROS
Yongyi Xie1, Zile Chen1, Zhouwei Wu1
1Department of Dermatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
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.
Insights
4-octyl itaconate (4-OI) protects skin cells from UVB damage by reducing reactive oxygen species (ROS) and activating the Nrf2 pathway. This compound shows potential for treating oxidative stress-related skin disorders like vitiligo.
Area of Science:
- Dermatology
- Cell Biology
- Oxidative Stress Research
Background:
- Vitiligo is an acquired skin depigmentation disease where excessive reactive oxygen species (ROS) cause melanocyte destruction.
- The interaction between melanocytes and keratinocytes is crucial, suggesting treatments protecting both cell types may be beneficial.
Purpose of the Study:
- To investigate the protective effects of 4-octyl itaconate (4-OI) against ultraviolet B (UVB)-induced apoptosis in HaCaT and PIG1 cells.
- To elucidate the underlying mechanisms, including ROS reduction and the role of the Nrf2 pathway.
Main Methods:
- HaCaT and PIG1 cells were pretreated with 4-OI before UVB exposure.
- ROS levels and apoptosis were measured using fluorescence microscopy and flow cytometry.
- Protein and mRNA expression, and nuclear translocation were analyzed via confocal microscopy, western blotting, and qRT-PCR.
- In vivo studies utilized the Institute of Cancer Research (ICR) mouse model.
Main Results:
- UVB exposure induced apoptosis in HaCaT and PIG1 cells, which was reversed by inhibiting ROS production.
- 4-OI significantly reduced UVB-induced apoptosis in a concentration-dependent manner by decreasing ROS levels.
- 4-OI promoted nuclear translocation and activation of nuclear factor erythroid 2-related factor 2 (Nrf2).
- Nrf2 silencing counteracted the protective effects of 4-OI.
- In vivo, 4-OI treatment reduced UVB-induced skin damage in mice.
Conclusions:
- 4-octyl itaconate (4-OI) protects melanocytes and keratinocytes from UVB-induced apoptosis.
- The protective mechanism involves Nrf2 activation-dependent inhibition of ROS.
- 4-OI demonstrates potential as a therapeutic agent for skin disorders linked to oxidative stress, such as vitiligo.
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