Nrf2—A regulator of keratinocyte redox signaling

doi:10.1016/j.freeradbiomed.2015.04.018

Free Radical Biology and Medicine

Volume 88, Part B, November 2015, Pages 243-252

https://doi.org/10.1016/j.freeradbiomed.2015.04.018 Get rights and content

Highlights

•
Nrf2 protects keratinocytes from UV toxicity and from toxic chemicals.
•
Nrf2 in keratinocytes is essential for skin cancer prevention.
•
Nrf2 activation promotes repair of a defective epidermis.
•
Chronic Nrf2 activation has detrimental effects on the skin.
•
Gain- or loss-of-function of Nrf2 is associated with various human skin diseases.

Abstract

The skin is frequently exposed to environmental challenges, such as UV irradiation, toxic chemicals, and mechanical wounding. These insults cause an increase in the levels of reactive oxygen species, resulting in oxidative stress and concomitant inflammation, skin aging, and even cancer development. Therefore, an efficient antioxidant defense strategy is of major importance in this tissue. Since the Nrf2 transcription factor regulates a battery of genes involved in the defense against reactive oxygen species and in compound metabolism, it plays a key role in skin homeostasis, repair, and disease. In this review we summarize current knowledge on the expression and function of Nrf2 in normal skin and its role in the acute and chronic UV response as well as in the pathogenesis of epithelial skin cancer and of different inflammatory skin diseases. Finally, we discuss the potential of Nrf2-activating compounds for skin protection under stress conditions and for the treatment of major human skin disorders.

Introduction

Various human disorders are thought to be driven by oxidative stress, which is the result of an imbalance between the production and the detoxification of reactive oxygen species (ROS), resulting in an excess of these toxic molecules [1]. ROS are generated in all cells in the course of normal metabolic processes, e.g., in the respiratory chain, and low levels of ROS are required for cellular signaling. However, high levels of these aggressive molecules can damage cellular macromolecules, resulting in severe cell damage. This frequently initiates an inflammatory response and can even lead to neoplastic transformation [2]. Therefore, oxidative stress plays an important role in the pathogenesis of cancer and of different inflammatory and neurodegenerative diseases [3], [4]. To prevent or at least limit ROS-induced damage, cells are dependent on efficient ROS detoxification. This is achieved by low molecular weight antioxidants, such as vitamins C and E and the tripeptide glutathione, as well as by ROS-detoxifying enzymes and antioxidant proteins [2], [5]. Many cytoprotective proteins, including heme oxygenase 1 (HO-1), peroxiredoxins 1 and 6, NAPD(H) dehydrogenase, quinone 1 (NQO1), and the glutathione biosynthesis enzymes glutamate-cysteine ligase (regulatory and catalytic subunits) and glutathione synthetase, are under the control of nuclear factor erythroid 2-like 2 (Nrf2), a master regulator of the antioxidant response. Nrf2 is a member of the cap’n’collar family of basic leucine zipper transcription factors, which also includes p45NF-E2, Nrf1, Nrf3, BACH1, and BACH2 [6]. The role of Nrf2 in the antioxidant response is remarkable. Under normal conditions, the Nrf2 antagonist Keap1 retains Nrf2 in the cytoplasm and also mediates its ubiquitination and subsequent proteasomal degradation. Activation of Nrf2 occurs predominantly through conformational changes of Keap1, which are induced by coupling of electrophiles to this protein via Michael addition. This results in stabilization of Nrf2 and subsequent saturation of the Keap1 binding sites. In addition, it has been suggested that ROS activate certain kinases that phosphorylate Nrf2, resulting in weakening of the Keap1–Nrf2 interaction. Newly synthetized Nrf2 is then able to translocate to the nucleus and to dimerize with small Maf proteins. These heterodimers bind to antioxidant response elements (AREs) in the promoters of Nrf2 target genes and activate their expression [6], [7].

Efficient ROS detoxification is particularly important in the skin, which is frequently challenged by ultraviolet (UV) light as well as by mechanical insults or exposure to various irritants, allergens, and pathogens [8]. These insults result in the generation of high levels of ROS through activation of NADPH oxidase in keratinocytes and attraction of neutrophils and macrophages, which are particularly efficient ROS producers. In addition, ROS are generated during the course of metabolism/detoxification of various chemical compounds. Therefore, a functional Nrf2 protein is of major importance in the skin. Here we report on the expression and function of Nrf2 in normal skin and under various pathological conditions. We focus on the role of Nrf2 in keratinocytes, which has been particularly well studied, but roles in other cutaneous cell types will also be addressed if they are relevant for the interpretation of in vivo data.

Section snippets

Nrf2 in skin homeostasis

The skin is composed of three layers, including the epidermis, the dermis, and the underlying subcutaneous fat layer (hypodermis) (Fig. 1A). Studies from various laboratories demonstrated expression of Nrf2 in all cell types of the skin, whereby its role in keratinocytes has been particularly well described. Interestingly, a gradient of Nrf2 expression and activity was detected in the murine epidermis, and differentiated, suprabasal cells were shown to express significantly higher levels of

Regulation of Nrf2 by UVA and UVB

The important role of Nrf2 in the cellular antioxidant defense raised excitement about the potential usefulness of this transcription factor as a target for photoprotection. As a first step to address this question, several laboratories determined if and to what extent UVA and UVB light, which both increase the levels of intracellular ROS, affect the expression and/or activity of Nrf2. Kannan and Jaiswal demonstrated that a very low dose of UVB (0.75 mJ/cm²) induced nuclear accumulation of Nrf2

Pharmacological activation of Nrf2 for protection of skin from toxic compounds

Due to the potent activity of Nrf2 in ROS and compound detoxification, Nrf2-activating compounds have also been tested in chemical toxicity studies with cultured keratinocytes. A major toxin and carcinogen for keratinocytes is inorganic arsenite, which induces hyperkeratosis and promotes skin carcinogenesis. Interestingly, treatment of human keratinocytes with the Nrf2-activating compounds curcumin or tert-butylhydroquinone protected cells from arsenite-induced cytotoxicity and apoptosis [34],

The role of Nrf2 in skin carcinogenesis

The important role of Nrf2 in the protection from ROS-induced damage in response to UV irradiation or exposure to toxic chemicals as well as its direct effect on the expression of genes involved in compound detoxification suggests that Nrf2 activation can be a promising strategy for cancer prevention. However, the same protective mechanisms may also protect existing cancer cells, thereby increasing cancer progression and drug/radiation resistance. This topic has been extensively studied for

Nrf2 in wound healing and in repair of a defective epidermis

There are major parallels between wound healing and cancer [71], and therefore, the role of Nrf2 in the wound healing process is particularly interesting. A role of Nrf2 in cutaneous wound healing was first suggested by the upregulation of this gene in response to full-thickness excisional wounding in mice [13]. When Nrf2 knockout mice were subjected to full-thickness excisional wounding, wound closure was not obviously affected. However, the inflammatory response was delayed and prolonged, in

Role of Nrf2 in atopic dermatitis, psoriasis, and epidermal blistering diseases.

In addition to sulforaphane, repair of an impaired epidermal barrier was promoted by coal tar. In this study, the authors used skin explants and organotypic skin cultures of keratinocytes from atopic dermatitis patients and treated them topically with coal tar. This treatment restored the levels of the cornified envelope protein filaggrin to normal levels and ameliorated other molecular and histological hallmarks of the disease. Although the primary target of this treatment is AHR, a role of

Role of Nrf2 in allergic skin inflammation

A common inflammatory skin disease is allergic contact dermatitis, which develops on contact of the skin with small chemicals, drugs, or cosmetics, which covalently interact with proteins. Interestingly, increased ROS levels have been found on treatment with different contact sensitizers [84], suggesting a role of Nrf2 in the cutaneous inflammation that develops on contact of the skin with the chemical. Indeed, studies with Nrf2 knockout mice revealed that the threshold for an inflammatory

A potential role of activated Nrf2 in ichthyosis and chloracne (MADISH)

The above-described results revealed beneficial effects of Nrf2-activating compounds on repair of a defective epidermal barrier. By contrast, long-term activation of Nrf2 in the context of a normal barrier was shown to be detrimental. This was first demonstrated by the phenotype of Keap1 knockout mice, which die early after birth from hyperkeratosis in the esophagus. Severe scaling was also seen in the skin of these mice, and the phenotype in skin and esophagus was rescued by concomitant loss

A role of defective Nrf2 signaling in the pathogenesis of vitiligo vulgaris?

Vitiligo vulgaris is a pigment disorder that results from the inability of melanocytes to produce melanin and/or from apoptosis of these cells. As a result, various areas of the body progressively lose their pigmentation, resulting in the appearance of white spots. A role of Nrf2 in the pathogenesis of this disease was suggested by the finding that a polymorphism in the Nrf2 gene promoter is associated with the development of the disease in a Chinese population [91]. There are conflicting

Conclusions

A series of studies have provided evidence for an important role of Nrf2 in skin homeostasis, repair, and disease. In most of these studies, the loss of Nrf2 had negative consequences, strongly suggesting that keratinocytes depend on a functional Nrf2 gene to prevent excessive skin inflammation and development of skin tumors in response to various challenges. Since this important activity strongly suggests that further activation of Nrf2 is beneficial, various Nrf2-activating compounds have

Acknowledgments

Research on Nrf2 in our laboratory is supported by the ETH Zurich, the Swiss National Science Foundation (310030_132884 to S.W.), the Wilhelm Sander-Stiftung (to S.W.), Cancer Research Switzerland (KFS 2822-08-2011 to S.W.), and the Gebert-Rüf-Stiftung (GRS-052/13 to M.S. and S.W.).

References (94)

M.L. Circu et al.
Reactive oxygen species, cellular redox systems, and apoptosis
Free Radic. Biol. Med.
(2010)
K. Hensley et al.
Reactive oxygen species, cell signaling, and cell injury
Free Radic. Biol. Med.
(2000)
M. Schäfer et al.
Oxidative stress in normal and impaired wound repair
Pharmacol. Res.
(2008)
D.R. Bickers et al.
Oxidative stress in the pathogenesis of skin disease
J. Invest. Dermatol.
(2006)
M.S. Piao et al.
Differentiation-dependent expression of NADP(H):quinone oxidoreductase-1 via NF-E2 related factor-2 activation in human epidermal keratinocytes
J. Dermatol. Sci.
(2011)
M. Durchdewald et al.
Electrophilic chemicals but not UV irradiation or reactive oxygen species activate Nrf2 in keratinocytes in vitro and in vivo
J. Invest. Dermatol.
(2007)
Y. Zhao et al.
Autophagy is induced by UVA and promotes removal of oxidized phospholipids and protein aggregates in epidermal keratinocytes
J. Invest. Dermatol.
(2013)
A. Hirota et al.
Ultraviolet A irradiation induces NF-E2-related factor 2 activation in dermal fibroblasts: protective role in UVA-induced apoptosis
J. Invest. Dermatol.
(2005)
Y. Kawachi et al.
Attenuation of UVB-induced sunburn reaction and oxidative DNA damage with no alterations in UVB-induced skin carcinogenesis in Nrf2 gene-deficient mice
J. Invest. Dermatol.
(2008)
K. Kleszczynski et al.
Sulforaphane and phenylethyl isothiocyanate protect human skin against UVR-induced oxidative stress and apoptosis: role of Nrf2-dependent gene expression and antioxidant enzymes
Pharmacol. Res.
(2013)

J.A. Sirerol et al.

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

Free Radic. Biol. Med.

(2015)

J. Pi et al.

Transcription factor Nrf2 activation by inorganic arsenic in cultured keratinocytes: involvement of hydrogen peroxide

Exp. Cell Res.

(2003)

J. Pi et al.

Arsenic-induced malignant transformation of human keratinocytes: involvement of Nrf2

Free Radic. Biol. Med.

(2008)

Y. Sun et al.

Arsenic transformation predisposes human skin keratinocytes to UV-induced DNA damage yet enhances their survival apparently by diminishing oxidant response

Toxicol. Appl. Pharmacol.

(2011)

G. Tsuji et al.

Identification of ketoconazole as an AhR-Nrf2 activator in cultured human keratinocytes: the basis of its anti-inflammatory effect

J. Invest. Dermatol.

(2012)

E.L. Abel et al.

Protection against 2-chloroethyl ethyl sulfide (CEES)-induced cytotoxicity in human keratinocytes by an inducer of the glutathione detoxification pathway

Toxicol. Appl. Pharmacol.

(2011)

J. Soeur et al.

Skin resistance to oxidative stress induced by resveratrol: from Nrf2 activation to GSH biosynthesis

Free Radic. Biol. Med.

(2015)

F. Lieder et al.

Identification of UV-protective activators of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) by combining a chemical library screen with computer-based virtual screening

J. Biol. Chem.

(2012)

G.T. Wondrak et al.

Cinnamoyl-based Nrf2-activators targeting human skin cell photo-oxidative stress

Free Radic. Biol. Med.

(2008)

Y.C. Hseu et al.

Ellagic acid protects human keratinocyte (HaCaT) cells against UVA-induced oxidative stress and apoptosis through the upregulation of the HO-1 and Nrf-2 antioxidant genes

Food Chem. Toxicol.

(2012)

K.J. Rodriguez et al.

A purified feverfew extract protects from oxidative damage by inducing DNA repair in skin cells via a PI3-kinase-dependent Nrf2/ARE pathway

J. Dermatol. Sci.

(2013)

S. Kimura et al.

Essential role of Nrf2 in keratinocyte protection from UVA by quercetin

Biochem. Biophys. Res. Commun.

(2009)

Y. Liu et al.

Resveratrol protects human keratinocytes HaCaT cells from UVA-induced oxidative stress damage by downregulating Keap1 expression

Eur. J. Pharmacol.

(2011)

S.H. Yuspa

The pathogenesis of squamous cell cancer: lessons learned from studies of skin carcinogenesis

J. Dermatol. Sci.

(1998)

J.J. Gills et al.

Sulforaphane prevents mouse skin tumorigenesis during the stage of promotion

Cancer Lett.

(2006)

A.T. Dinkova-Kostova et al.

Protection against UV-light-induced skin carcinogenesis in SKH-1 high-risk mice by sulforaphane-containing broccoli sprout extracts

Cancer Lett.

(2006)

P.J. Dziunycz et al.

The oncogene ATF3 is potentiated by cyclosporine A and ultraviolet light A

J. Invest. Dermatol.

(2014)

Y.R. Kim et al.

Oncogenic Nrf2 mutations in squamous cell carcinomas of oesophagus and skin

J. Pathol.

(2010)

Y. Mitsuishi et al.

Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming

Cancer Cell

(2012)

N. Oshimori et al.

TGF-beta promotes heterogeneity and drug resistance in squamous cell carcinoma

Cell

(2015)

A.J. Huebner et al.

Amniotic fluid activates the nrf2/keap1 pathway to repair an epidermal barrier defect in utero

Dev. Cell

(2012)

W.P. Vermeij et al.

ROS quenching potential of the epidermal cornified cell envelope

J. Invest. Dermatol.

(2011)

R. Emter et al.

Gene expression changes induced by skin sensitizers in the KeratinoSens cell line: discriminating Nrf2-dependent and Nrf2-independent events

Toxicol. In Vitro

(2013)

J.Y. Kim et al.

Protease-activated receptor-2 activates NQO-1 via Nrf2 stabilization in keratinocytes

J. Dermatol. Sci.

(2014)

V.T. Natarajan et al.

Transcriptional upregulation of Nrf2-dependent phase II detoxification genes in the involved epidermis of vitiligo vulgaris

J. Invest. Dermatol.

(2010)

Z. Jian et al.

Impaired activation of the Nrf2-ARE signaling pathway undermines H₂O₂-induced oxidative stress response: a possible mechanism for melanocyte degeneration in vitiligo

J. Invest. Dermatol.

(2014)

H. Sies

Oxidative stress: oxidants and antioxidants

Exp. Physiol.

(1997)

A. Federico et al.

Chronic inflammation and oxidative stress in human carcinogenesis

Int. J. Cancer

(2007)

G.P. Sykiotis et al.

Stress-activated cap’n’collar transcription factors in aging and human disease

Sci. Signal.

(2010)

H. Motohashi et al.

Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway

Proc. Natl. Acad. Sci. USA

(2004)

M. Schäfer et al.

Nrf2: a central regulator of UV protection in the epidermis

Cell Cycle

(2010)

Y. Lee et al.

Role of nuclear factor E2-related factor 2 (Nrf2) in epidermal differentiation

Arch. Dermatol. Res.

(2014)

M.S. Piao et al.

Nrf2-dependent and Nrf2-independent induction of phase 2 detoxifying and antioxidant enzymes during keratinocyte differentiation

Arch. Dermatol. Res.

(2012)

S. Braun et al.

Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound

Mol. Cell. Biol.

(2002)

U. auf dem Keller et al.

Nrf transcription factors in keratinocytes are essential for skin tumor prevention but not for wound healing

Mol. Cell. Biol.

(2006)

S. Kannan et al.

Low and high dose UVB regulation of transcription factor NF-E2-related factor 2

Cancer Res.

(2006)

S.K. Niture et al.

Src subfamily kinases regulate nuclear export and degradation of transcription factor Nrf2 to switch off Nrf2-mediated antioxidant activation of cytoprotective gene expression

J. Biol. Chem.

(2011)

Cited by (149)

Live-cell imaging Unveils stimulus-specific dynamics of Nrf2 activation in UV-exposed melanoma cells: Implications for antioxidant compound screening
2024, Free Radical Biology and Medicine
The transcription factor Nuclear factor e2-related factor 2 (Nrf2) is pivotal in orchestrating cellular antioxidant defense mechanisms, particularly in skin cells exposed to ultraviolet (UV) radiation and electrophilic phytochemicals. To comprehensively investigate Nrf2's role in maintaining cellular redox equilibrium following UV-induced stress, we engineered a novel Nrf2 fusion-based reporter system for real-time, live-cell quantification of Nrf2 activity in human melanoma cells. Utilizing live quantitative imaging, we dissected the kinetic profiles of Nrf2 activation in response to an array of stimuli, including UVA and UVB radiation, as well as a broad spectrum of phytochemicals including ferulic acid, gallic acid, hispidulin, p-coumaric acid, quercetin, resveratrol, tannic acid, and vanillic acid as well as well-known Nrf2 inducers, tert-butylhydroquinone (tBHQ) and sulforaphane (SFN). Intriguingly, we observed distinct dynamical patterns of Nrf2 activity contingent on the specific stimuli applied. Sustained activation of Nrf2 was empirically correlated with the increased antioxidant response element (ARE) activity. Our findings demonstrate the nuanced impact of different phenolic compounds on Nrf2 activity and the utility of our Nrf2-CTΔ16-YFP reporter in characterizing the dynamics of Nrf2 translocation in response to diverse stimuli. In summary, our innovative reporter system not only revealed compounds capable of modulating UVA-induced Nrf2 activity but also showcased its utility as a robust tool for future antioxidant compound screening efforts.
Exogenous drugs-induced mouse models of atopic dermatitis
2024, Cytokine and Growth Factor Reviews
Atopic dermatitis (AD) is an inflammatory skin disease characterized by intense pruritus. AD is harmful to both children and adults, but its pathogenic mechanism has yet to be fully elucidated. The development of mouse models for AD has greatly contributed to its study and treatment. Among these models, the exogenous drug-induced mouse model has shown promising results and significant advantages. Until now, a large amount of AD-related research has utilized exogenous drug-induced mouse models, leading to notable advancements in research. This indicates the crucial significance of applying such models in AD research. These models exhibit diverse characteristics and are highly complex. They involve the use of various strains of mice, diverse types of inducers, and different modeling effects. However, there is currently a lack of comprehensive comparative studies on exogenous drug-induced AD mouse models, which hinders researchers' ability to choose among these models. This paper provides a comprehensive review of the features and mechanisms associated with various exogenous drug-induced mouse models, including the important role of each cytokine in AD development. It aims to assist researchers in quickly understanding models and selecting the most suitable one for further investigation.
Cold atmospheric plasma alleviates radiation-induced skin injury by suppressing inflammation and promoting repair
2023, Free Radical Biology and Medicine
Currently, there is no effective treatment for chronic skin radiation injury, which burdens patients significantly. Previous studies have shown that cold atmospheric plasma has an apparent therapeutic effect on acute and chronic skin injuries in clinical. However, whether CAP is effective for radiation-induced skin injury has not been reported. We created 35Gy X-ray radiation exposure within 3 * 3 cm² region of the left leg of rats and applied CAP to the wound bed. Wound healing, cell proliferation and apoptosis were examined in vivo or vitro. CAP alleviated radiation-induced skin injury by enhancing proliferation and migration and cellular antioxidant stress and promoting DNA damage repair through regulated nuclear translocation of NRF2. In addition, CAP inhibited the proinflammatory factors' expression of IL-1β, TNF-α and temporarily increased the pro repair factor's expression of IL-6 in irradiated tissues. At the same time, CAP also changed the polarity of macrophages to a repair-promoting phenotype. Our finding suggested that CAP ameliorated radiation-induced skin injury by activating NRF2 and ameliorating the inflammatory response. Our work provided a preliminary theoretical foundation for the clinical administration of CAP in high-dose irradiated skin injury.
Functions of the aryl hydrocarbon receptor (AHR) beyond the canonical AHR/ARNT signaling pathway
2023, Biochemical Pharmacology
The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor regulating adaptive and maladaptive responses toward exogenous and endogenous signals. Research from various biomedical disciplines has provided compelling evidence that the AHR is critically involved in the pathogenesis of a variety of diseases and disorders, including autoimmunity, inflammatory diseases, endocrine disruption, premature aging and cancer. Accordingly, AHR is considered an attractive target for the development of novel preventive and therapeutic measures. However, the ligand-based targeting of AHR is considerably complicated by the fact that the receptor does not always follow the beaten track, i.e. the canonical AHR/ARNT signaling pathway. Instead, AHR might team up with other transcription factors and signaling molecules to shape gene expression patterns and associated physiological or pathophysiological functions in a ligand-, cell- and micromilieu-dependent manner. Herein, we provide an overview about some of the most important non-canonical functions of AHR, including crosstalk with major signaling pathways involved in controlling cell fate and function, immune responses, adaptation to low oxygen levels and oxidative stress, ubiquitination and proteasomal degradation. Further research on these diverse and exciting yet often ambivalent facets of AHR biology is urgently needed in order to exploit the full potential of AHR modulation for disease prevention and treatment.
Driving adult tissue repair via re-engagement of a pathway required for fetal healing
2023, Molecular Therapy
Fetal cutaneous wound closure and repair differ from that in adulthood. In this work, we identify an oxidant stress sensor protein, nonselenocysteine-containing phospholipid hydroperoxide glutathione peroxidase (NPGPx), that is abundantly expressed in normal fetal epidermis (and required for fetal wound closure), though not in adult epidermis, but is variably re-induced upon adult tissue wounding. NPGPx is a direct target of the miR-29 family. Following injury, abundance of miR-29 is lowered, permitting a prompt increase in NPGPx transcripts and protein expression in adult wound-edge tissue. NPGPx expression was required to mediate increased keratinocyte migration induced by miR-29 inhibition in vitro and in vivo. Increased NPGPx expression induced increased SOX2 expression and β-catenin nuclear localization in keratinocytes. Augmenting physiologic NPGPx expression via experimentally induced miR-29 suppression, using cutaneous tissue nanotransfection or targeted lipid nanoparticle delivery of anti-sense oligonucleotides, proved to be sufficient to overcome the deleterious effects of diabetes on this specific pathway to enhance tissue repair.
Therapeutic efficacy of Scutellaria baicalensis Georgi against psoriasis-like lesions via regulating the responses of keratinocyte and macrophage
2022, Biomedicine and Pharmacotherapy
Psoriasis is a chronic and recurrent skin problem that affects 3% of the global population. Nowadays, most medicines may not promise a complete cure for patients with psoriasis because of the development of pharmacoresistance and the side effects of drugs due to the microenvironment impact in the context of skin imbalance. Herein, we attempt to explore the pharmaceutical efficacy of Scutellaria baicalensis (S. baicalensis) in modulating the microenvironment created by macrophages and keratinocytes in psoriasis. The results indicated that treatment of S. baicalensis extract significantly reduced the thickness of epidermis and attenuated psoriatic lesions. Moreover, S. baicalensis extract obviously inhibited the activation and infiltration of macrophages by alleviating inflammatory factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and cyclooxygenase-2 (COX-2). The administration of S. baicalensis extract also remarkably abolished oxidative damage upon DNA and proteins, which attributed to the activation of nuclear factor erythroid 2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1). The network analysis of redox proteomics and cytokine profiles suggested that S. baicalensis administration regulated the specific pathways associated with oxidative stress, inflammation and cytokine signaling cascades to ameliorate the macrophage-targeted responses and subsequently arrest proliferation of keratinocytes. Collectively, our findings highlighted the importance of S. baicalensis application in reprogramming microenvironment to provide an alternative and complementary intervention for long-term psoriatic therapy.

View all citing articles on Scopus

View full text

Nrf2—A regulator of keratinocyte redox signaling

Highlights

Abstract

Introduction

Section snippets

Nrf2 in skin homeostasis

Regulation of Nrf2 by UVA and UVB

Pharmacological activation of Nrf2 for protection of skin from toxic compounds

The role of Nrf2 in skin carcinogenesis

Nrf2 in wound healing and in repair of a defective epidermis

Role of Nrf2 in atopic dermatitis, psoriasis, and epidermal blistering diseases.

Role of Nrf2 in allergic skin inflammation

A potential role of activated Nrf2 in ichthyosis and chloracne (MADISH)

A role of defective Nrf2 signaling in the pathogenesis of vitiligo vulgaris?

Conclusions

Acknowledgments

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Pharmacol. Res.

J. Invest. Dermatol.

J. Dermatol. Sci.

J. Invest. Dermatol.

J. Invest. Dermatol.

J. Invest. Dermatol.

J. Invest. Dermatol.

Pharmacol. Res.

Free Radic. Biol. Med.

Exp. Cell Res.

Free Radic. Biol. Med.

Toxicol. Appl. Pharmacol.

J. Invest. Dermatol.

Toxicol. Appl. Pharmacol.

Free Radic. Biol. Med.

J. Biol. Chem.

Free Radic. Biol. Med.

Food Chem. Toxicol.

J. Dermatol. Sci.

Biochem. Biophys. Res. Commun.

Eur. J. Pharmacol.

J. Dermatol. Sci.

Cancer Lett.

Cancer Lett.

J. Invest. Dermatol.

J. Pathol.

Cancer Cell

Cell

Dev. Cell

J. Invest. Dermatol.

Toxicol. In Vitro

J. Dermatol. Sci.

J. Invest. Dermatol.

J. Invest. Dermatol.

Oxidative stress: oxidants and antioxidants

Exp. Physiol.

Chronic inflammation and oxidative stress in human carcinogenesis

Int. J. Cancer

Stress-activated cap’n’collar transcription factors in aging and human disease

Sci. Signal.

Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway

Proc. Natl. Acad. Sci. USA

Nrf2: a central regulator of UV protection in the epidermis

Cell Cycle

Role of nuclear factor E2-related factor 2 (Nrf2) in epidermal differentiation

Arch. Dermatol. Res.

Nrf2-dependent and Nrf2-independent induction of phase 2 detoxifying and antioxidant enzymes during keratinocyte differentiation

Arch. Dermatol. Res.

Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound

Mol. Cell. Biol.

Nrf transcription factors in keratinocytes are essential for skin tumor prevention but not for wound healing

Mol. Cell. Biol.

Low and high dose UVB regulation of transcription factor NF-E2-related factor 2

Cancer Res.

Src subfamily kinases regulate nuclear export and degradation of transcription factor Nrf2 to switch off Nrf2-mediated antioxidant activation of cytoprotective gene expression

J. Biol. Chem.