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Abstract
Nrf2 plays a critical role in defending against oxidative stress and inflammation. We previously reported that Nrf2 confers protection against ultraviolet-B (UVB)-induced inflammation, sunburn reaction, and is involved in sulforaphane-mediated photo-protective effects in the skin. In this study, we aimed to demonstrate the protective role of Nrf2 against inflammation-mediated extracellular matrix (ECM) damage induced by UVB irradiation. Ear biopsy weights were significantly increased in both Nrf2 wild-type (Nrf2 WT) and knockout (Nrf2 KO) mice one week after UVB irradiation. However, these weights increased more significantly in KO mice compared to WT mice, suggesting a greater inflammatory response in KO mice. In addition, we analyzed the protein expression of numerous markers, including macrophage inflammatory protein-2 (MIP-2), pro-matrix metalloproteinase-9 (MMP-9), and p53. p53, a regulator of DNA repair, was overexpressed in Nrf2 KO mice, indicating that the absence of Nrf2 led to more sustained DNA damage. There was also more substantial ECM degradation and increased inflammation in UVB-irradiated Nrf2 KO mice compared to UVB-irradiated WT mice. Furthermore, the protective effects of Nrf2 in response to UVB irradiation were mediated by increased HO-1 protein expression. Collectively, our results show that Nrf2 plays a key role in protecting against UVB irradiation and that the photo-protective effect of Nrf2 is closely related to the inhibition of ECM degradation and inflammation.
Highlights
The incidence of non-melanoma skin cancer has steadily increased, and ultraviolet (UV) light is one of the major causes of non-melanoma skin cancer
We previously reported the critical role of nuclear Nrf2 in the classical 2-stage model of skin carcinogenesis induced by the chemical carcinogen 7,12-dimethylbenz(a) anthracene (DMBA) and the tumor promoter TPA in Nrf2 knockout (Nrf2 KO) and wild-type (WT) mice [19]
The results presented here demonstrated that UVB exposure significantly increased the ear biopsy weight in Nrf2 KO mice by almost 100%, whereas the ear biopsy weight only increased by 16% in Nrf2 wild-type (Nrf2 WT) mice
Summary
The incidence of non-melanoma skin cancer has steadily increased, and ultraviolet (UV) light is one of the major causes of non-melanoma skin cancer. Altered ECM metabolism has been implicated in various diseases [5] Oxidative stress, such as that caused by excessive reactive oxygen species (ROS), is caused by UVB damage to DNA, protein, and lipids and can lead to inflammation, gene mutation, and immunosuppression [6,7]. HO-1 exhibits broad cytoprotective effects in various inflammatory diseases [9] and was shown to play a critical protective role in limiting oxidative damage in a UVB-induced model [10]. It has been reported that the disruption of Nrf enhanced the upregulation of key inflammatory transcription factors, such as nuclear factor kappa B (NF-κB) and MMP-9 [12], and increased expression of macrophage inflammatory protein-2 (MIP-2), a neutrophil chemotactic factor, was observed in response to 12-O-tetradecanoylphorbol-13-acetate (TPA)induced epidermal hyperplasia in mice [13]. P53 is known to be activated by DNA damage [14], oxidative stress [16], and inflammation [17,18]
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