The role of transcription factor Nrf2 in skin cells metabolism

Abstract

Skin, which is a protective layer of the body, is in constant contact with physical and chemical environmental factors. Exposure of the skin to highly adverse conditions often leads to oxidative stress. Moreover, it has been observed that skin cells are also exposed to reactive oxygen species generated during cell metabolism particularly in relation to the synthesis of melanin or the metabolism in immune system cells. However, skin cells have special features that protect them against oxidative modifications including transcription factor Nrf2, which is responsible for the transcription of the antioxidant protein genes such as antioxidant enzymes, small molecular antioxidant proteins or interleukins, and multidrug response protein. In the present study, the mechanisms of Nrf2 activation have been compared in the cells forming the various layers of the skin: keratinocytes, melanocytes, and fibroblasts. The primary mechanism of control of Nrf2 activity is its binding by cytoplasmic inhibitor Keap1, while cells have also other controlling mechanisms, such as phosphorylation of Nrf2 and modifications of its activators (e.g., Maf, IKKβ) or inhibitors (e.g., Bach1, caveolae, TGF-β). Moreover, there are a number of drugs (e.g., ketoconazole) used in the pharmacotherapy of skin diseases based on the activation of Nrf2, but they may also induce oxidative stress. Therefore, it is important to look for compounds that cause a selective activation of Nrf2 particularly natural substances such as curcumin, sulforaphane, or extracts from the broccoli leaves without side effects. These findings could be helpful in the searching for new drugs for people with vitiligo or even melanoma.

Antioxidants for Healthy Skin: The Emerging Role of Aryl Hydrocarbon Receptors and Nuclear Factor-Erythroid 2-Related Factor-2

“…The transcription factor NRF2 is a master switch for inducing antioxidant enzymes and is expressed in epidermal keratinocytes at high levels [16,17,31,32]. The antioxidant enzymes downstream of NRF2 include NQO1, HO-1, glutathione S-transferase, UDP-glucuronosyltransferases, epoxide hydrolase, glutathione reductase, thioredoxin reductase, catalase, and superoxide dismutase.…”

“…The antioxidant enzymes downstream of NRF2 include NQO1, HO-1, glutathione S-transferase, UDP-glucuronosyltransferases, epoxide hydrolase, glutathione reductase, thioredoxin reductase, catalase, and superoxide dismutase. NRF2 also activates the transcription of non-enzymatic antioxidant protein genes, such as thioredoxin and ferritin [17]. Under physiological conditions, the level of NRF2 in the cytoplasm is regulated by the formation of the NRF2-KEAP1-CUL3 complex [17].…”

“…The antioxidant molecules, including glutathione, vitamin E, and vitamin C work together with enzymatic antioxidants, such as NAD(P)H:quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), and glutathione S-transferase [17]. The induction of these antioxidant enzymes is regulated by nuclear factor-erythroid 2-related factor-2 (NRF2), which is a master switch for antioxidant signaling [13,17]. …”

Dysfunction of Autophagy: A Possible Mechanism Involved in the Pathogenesis of Vitiligo by Breaking the Redox Balance of Melanocytes

“…External and internal sources of oxidative stress include UVR/IR, pollution (environment), lifestyle (exercise and diet), alcohol, and smoking all of which may potentially have impacts on skin [55]. All these factors, leading to an increase in ROS generation and/or a reduction in the antioxidant capacity, contribute to oxidative stress, which exposes the skin cells to the formation and accumulation of irreversibly damaged proteins, lipids, nucleic acids, and carbohydrates [56]. Human skin is exposed to environmental insults such as UV light that cause oxidative damage to macromolecules.…”

Photosensitizers Imprinting Intracellular Signaling Pathways in Dermato-Oncology Therapy

“…Also, in fibroblasts, NRF2 protects against differentiation and fibrosis processes; therefore, NRF2 activity could be modulated in the context of skin diseases pharmacotherapy and in PDT in order to improve the PDT efficacy by impairing adaptation of target cells to oxidative stress. In addition, NRF2 could be a key biomolecule in the searching for new drugs for various skin disorders including vitiligo or even cutaneous melanoma [75].…”