Nrf2 null enhances UVB-induced skin inflammation and extracellular matrix damages

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.

Topical treatment with pterostilbene, a natural phytoalexin, effectively protects hairless mice against UVB radiation-induced skin damage and carcinogenesis

“…Nevertheless conclusive results would benefit of using knockout mice, which are experiments now underway in our lab. In this sense our results also are in agreement with a previous report by Saw et al [58] showing that Nrf2 null (C57BL/6 mice) enhances UVB (a single dose of 300 mJ/cm 2 )-induced skin inflammation and extracellular matrix damages. Moreover, recent findings also indicate that the tumor suppressor activity of p53 is related to its role in maintaining cellular redox by regulating cellular metabolism [51].…”

Nrf2 Activation by SK-119 Attenuates Oxidative Stress, UVB, and LPS-Induced Damage

“…These results are in line with several studies that reported the pivotal role of Nrf2 in the endogenous cellular protection response against the damaging effect of UVB. For example, Saw et al [46] have found that Nrf2-knockout mice were more susceptible to UVB-induced damage and mutagenesis. In addition, Nrf2 was suggested to be a key regulator in the complex interplay between keratinocytes and melanocytes under UVB radiation by a paracrine MAPK-dependent pathway [47].…”

Skin Redox Balance Maintenance: The Need for an Nrf2-Activator Delivery System

“…Exhibiting a wide spectrum of cytoprotective effects in a variety of skin models including inflammatory and UV-induced oxidative damage, HO-1 induction was suggested as a marker diagnosis of oxidative stress related conditions [68,69].…”

“…Compelling evidence indicates that these enzymes are of high importance maintaining skin redox balance homeostasis and protecting the epidermis against oxidative damage-related conditions and diseases, including skin erythema, inflammation, wound healing and skin cancers [14,69,74,75]. It was reported that patients suffering from actinic keratoses and basal cell carcinoma (BCCs), common non-melanoma skin cancer, had reduced levels of antioxidant enzymes in plasma or serum [76].…”