The Role of KEAP1-NRF2 System in Atopic Dermatitis and Psoriasis

The Kelch-like erythroid cell-derived protein with cap‘n’collar homology-associated protein 1 (KEAP1)-nuclear factor erythroid-2-related factor 2 (NRF2) system, a thiol-based sensor-effector apparatus, exerts antioxidative and anti-inflammatory effects and maintains skin homeostasis. Thus, NRF2 activation appears to be a promising treatment option for various skin diseases. However, NRF2-mediated defense responses may deteriorate skin inflammation in a context-dependent manner. Atopic dermatitis (AD) and psoriasis are two common chronic inflammatory skin diseases caused by a defective skin barrier, dysregulated immune responses, genetic predispositions, and environmental factors. This review focuses on the role of the KEAP1-NRF2 system in the pathophysiology of AD and psoriasis and the therapeutic approaches that utilize this system.


Introduction
The epidermis is the interface between an organism and its external environment. The stratum corneum (SC), the outermost layer of the epidermis, prevents dehydration and invasion of external pathogens and allergens. The Kelch-like erythroid cell-derived protein with cap'n'collar homology-associated protein 1 (KEAP1)-nuclear factor erythroid-2-related factor 2 (NRF2) system, a thiol-based sensor-effector apparatus, maintains skin reduction-oxidation (redox) balance [1]. KEAP1 senses oxidative damage through reactive cysteine residues and activates NRF2-mediated antioxidative responses in keratinocytes (KCs) [2]. A previous study showed that Keap1-knockout mice display constitutive nuclear accumulation of NRF2 and exhibit weaning-age lethality, due to orthohyperkeratosis of the esophagus and forestomach, resulting in malnutrition [3]. To date, there has been an increasing amount of evidence that underscores the indispensable functions of the KEAP1-NRF2 system in epidermal keratinization and various skin disorders [4,5]. These studies suggest that NRF2 plays a key role in skin homeostasis [2].
Atopic dermatitis (AD) and psoriasis are two common chronic recurrent inflammatory skin disorders that affect a substantial number of patients worldwide and can compromise their quality of life. Both AD and psoriasis are characterized by a defective skin barrier, dysregulated immune responses (i.e., type 2 immunity or interleukin [IL]-4/IL-13 axis inflammation in AD and type 3 immunity or IL-23/IL-17 axis inflammation in psoriasis), genetic predispositions, and causative environmental factors [6,7]. Moreover, we have recently shown that impaired redox homeostasis in the epidermis may play a crucial role in the pathogenesis of AD and psoriasis [8,9].
Here, we review the significant roles of the KEAP1-NRF2 system in the pathophysiology of AD and psoriasis and the therapeutic approaches that utilize this system. We conducted a literature review by searching studies that examined the activation status of antimicrobial peptides [23,24]. Because NRF2 is a critical regulator of epidermal barrier function, as discussed later, KCs from Nrf2-knockout mice released significantly smaller amounts of IL-1α than that in wild-type KCs, and KEAP1 silencing in cultured normal human epidermal keratinocytes (NHEK) increased IL1A mRNA expression [8]. Therefore, NRF2 appears to regulate intracellular IL-1α expression levels in KCs. Similarly, NRF2 activation by tert-butylhydroquinone (TBHQ) in T cells skewed CD4 + T cells toward Th2 differentiation [25]. Collectively, NRF2 may promote IL-1α-type 2 immunity-mediated inflammatory responses to maintain skin homeostasis.

NRF2 as a Regulator of Keratinization
The epidermal tissue establishes a gradient of thiols, and free thiol (-SH) is effectively converted into disulfide (-S-S-) during terminal differentiation [29,30]. The redox status of protein thiol (-SH) in the differentiating layers appears to be central to the functionality of the protective barrier. For instance, SC is abundant in disulfide (-S-S-) cross-linkages, endowing the skin with mechanical resilience, as well as impermeability against pathogens and allergens [31]. The unique properties of SCs are attributed to the formation of cornified envelopes (CEs) [32], which replace the KC plasma cell membrane during the specialized cell death program termed cornification [33]. Loricrin (LOR), a thiol (-SH)-rich major CE protein [34], stabilizes the SC by inter/intra-molecular disulfide (-S-S-) cross-linkages and promotes structural maturation of the epidermal tissue [34]. Among the myriad xenobiotic metabolisms that govern epidermal homeostasis, the thiol-based sensor-effector apparatus KEAP1-NRF2 system appears to play a central role.
Several studies have demonstrated that NRF2 plays a crucial role in skin homeostasis. NRF2 ameliorated the ultraviolet (UV) response in the skin. Irradiation of Nrf2-knockout mice with UVB induced stronger and longer-lasting sunburn reactions with greater KCs apoptosis and oxidative damage than in control mice [38]. Similarly, transgenic mice expressing a caNrf2 mutant in KCs (K5cre-or K10caNrf2) showed attenuated UVB-induced KCs apoptosis and enhanced ROS detoxification [35]. NRF2 also protected the skin against the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) [39,40]. Furthermore, we have recently found that LOR and the KEAP1-NRF2 system coordinately upregulate robust antioxidative responses and exert xenobiotic metabolism in the epidermis [4,5,41]. In the absence of LOR, NRF2 directly upregulated thiol-rich CE proteins, small prolinerich protein 2 (SPRR2) [42], and late cornified envelope proteins [43], thereby compensating for the disrupted thiol gradient and epidermal barrier functions. Upon exposure to DMBA, LOR-knockout mice exhibited increased expression levels of NRF2 and DNA damage marker phospho-histone H2A.X, which were rescued by an oral administration of NAC [44]. These results suggest that thiol-rich LOR is indispensable for the antioxidative protection of the epidermis. Furthermore, NRF2-mediated adaptive responses evoked lamellar granule secretory functions and increased the expression of corneodesmosin, an extracellular component of corneodesmosomes [45], in LOR-knockout mice [46]. Therefore, NRF2 confers specialized antioxidative cytoprotection to the epidermis in coordination with LOR [2,37,39,[47][48][49].
Overall, NRF2 has beneficial effects on the epidermis under stress conditions (e.g., UV irradiation, chemical carcinogen exposure, and disrupted skin barriers). However, since Keap1-knockout mice and K5cre-or K10caNrf2 transgenic mice exhibited pathogenic hyperkeratosis, long-term unrestricted activation of NRF2 may have negative consequences [2].

Therapeutic Application of NRF2 Activators
NRF2 is a promising therapeutic target for oxidative stress-related diseases, such as autoimmune, respiratory, digestive, cardiovascular, metabolic, and neurodegenerative diseases, and cancer [50]. NRF2 activators or KEAP1 inhibitors include electrophiles, protein-protein interaction (PPI) inhibitors, and multi-target drugs (e.g., glycogen synthase kinase 3 inhibitors, HRD1 inhibitors, p62 activators, broad-complexes, tramtrack, bric-abrac domains, and CNC homolog 1 inhibitors) [51]. Most pharmacological NRF2 activators are electrophilic molecules [52], which include bardoxolone methyl (CDDO-Me) and its derivative (RTA-408), dimethyl fumarate (DMF), monomethyl fumarate (MMF) derivative (ALKS-8700), and sulforaphane and its derivatives (SFX-01 and ITH12674) [51]. Other examples of electrophiles are TBHQ, diethyl maleate, TFM-735, and nitric oxide, although most of these compounds are still far from being used in a clinical setting [51]. TBHQ, a wellrecognized electrophilic NRF2 activator, is widely used as a preservative in food because it prevents the rancidification of lipids [53]. Meanwhile, there has been an increasing interest in non-electrophilic modulators, such as PPI inhibitors, which prevent the docking of NRF2 to KEAP1 and may be more selective than electrophilic NRF2 activators [54]. However, NRF2 has controversial roles in cancer [55]; that is, NRF2 may be protective in the early stages of cancer but may be tumorigenic in the advanced stages (i.e., activated NRF2 may not only prevent ROS-induced oncogenic mutations, but also promote tumor cell survival by inhibiting apoptosis) [39]. Thus, the clinical application of NRF2 inhibitors has not been fully investigated.

NRF2 and Atopic Dermatitis
AD, also known as eczema or atopic eczema, is a common inflammatory skin disorder characterized by eczematous eruptions and intense itching [6]. AD affects over 20% of children [56] and 2.1-4.9% of adults [57] in industrialized countries. A family history of AD is associated with the development of AD [58], and filaggrin (FLG) mutations are associated with the strongest genetic risk for AD [59]. The pathogenesis of AD includes the interplay among skin barrier disruption, type 2 immunity, and pruritus [60], which can be targeted by innovative biological and small-molecule therapies. The emergence of dupilumab, an inhibitor of IL-4 and IL-13 signaling, has embodied this concept of "trinity" [61]. Topical and oral Janus kinase (JAK) inhibitors, such as delgocitinib, baricitinib, upadacitinib, and abrocitinib, have become promising treatment options for AD because they can block a battery of cytokines, growth factors, and hormone receptor signaling pathways that modulate the pathogenesis of AD [6]. AD can be accompanied by subsequent extracutaneous allergic diseases, such as asthma and allergic rhinitis [62]; therefore, early intervention with moisturizers for epicutaneous sensitization should be performed to prevent allergic march or atopic march [63].
Studies using mouse models of AD (e.g., epicutaneous application of sensitizers) [64] and analyses of human AD samples have revealed that NRF2 ameliorates AD inflammation ( Table 1).
As a therapeutic target, NRF2 activation by natural compounds or chemical agents can improve the inflammatory signal of human KCs in vitro or the phenotype of sensitizerinduced skin inflammation in mouse models that mimic human AD. The details are discussed in the following sections.

NRF2 Activators for AD
Coal tar, which consists of a variety of polycyclic aromatic hydrocarbons (PAHs) [65], has been used to treat skin diseases for more than 2000 years [66]. Coal tar induced aryl hydrocarbon receptor (AHR)-mediated NRF2 activation and epidermal differentiation and inhibited the IL-4/ signal transducer and activator of transcription (STAT) 6 signaling pathway, thereby improving AD-like inflammation in an organotypic skin model with primary KCs obtained from AD patients [66]. Igalan, a sesquiterpene lactone from Inula helenium (L.), suppressed the JAK/STAT3 signaling pathway and induced KC differentiation, thereby improving inflammatory cytokine (tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) or IL-4)-induced AD-like HaCaT cells [67].
Systemic application of NRF2 activators is also effective in mouse models of AD induced by DNCB, house dust mites (HDM), or trimellitic anhydride. The food and traditional oriental medicine Platycodon grandiflorum root-derived saponins (Changkil saponins) and its component platycodin D suppressed the NF-κB/STAT1 signaling pathway in HaCaT cells stimulated by TNF-α and IFN-γ [74]. 6-shogaol, a pungent compound isolated from ginger, inhibited ROS generation and mitogen-activated protein kinase signaling pathways in HaCaT cells and NHEK stimulated by TNF-α and IFN-γ [75]. Soshihotang [76] and Chijabyukpi-tang [77], traditional herbal medicines, inhibited pro-inflammatory cytokines and chemokines in mouse AD skin. The flavonoid quercetin, which is found in most edible fruits and vegetables, modulated the high-mobility group Box 1/receptor for advanced glycation end products/NF-κB signaling pathway in mouse AD skin [78]. Miquelianin, an active compound in Rosae multiflorae fructus, suppressed the proliferation of cultured CD4 + T cells isolated from splenocytes [79]. Collectively, NRF2 activators exert antioxidative and anti-inflammatory effects and ameliorate AD-like skin manifestations.

NRF2-Mediated Antioxidative Responses in the Epidermis and AD
In the lesional epidermis of human AD, however, NRF2 and its downstream target SPRR2 expression were elevated compared to the normal control epidermis, as shown by immunohistochemistry (IHC) analysis [8]. These findings were consistent with skin specimens from congenital skin disorders, such as Netherton syndrome (OMIM number 256,500) [80] and peeling skin syndrome (OMIM number 609,796) [81], which share similar features with AD [8]. Correspondingly, common environmental allergens, such as ovalbumin, HDM, and cedar pollen, stabilized NRF2 in cultured NHEKs, suggesting that skin sensitization would accompany NRF2 activation in the viable epidermal layers, which presumably takes place upon the disruption of the SC [8]. In contrast, in the peripheral blood of AD patients, protein expression level of NRF2 was downregulated compared to those in normal control patients. Kim et al. suggested that NRF2 downregulation enhances AD-associated inflammatory responses [82].
Consistent with these observations in human AD epidermis, we recently found that the immunogenicity of a hapten depends directly on NRF2-mediated antioxidant host defenses in the epidermis [8]. The specific chemical properties of haptens determine the nature of the immunological memory response. For example, immunogenic haptens, such as 1-fluoro-2,4-dinitrobenzene (DNFB) or DNCB, disrupted the reactive thiol layer in the SC, leading to dinitrophenylation and GSH depletion in the epidermis [83]. In contrast, tolerogenic haptens, such as 2,4-dinitrothiocyanobenzene (DNTB), induced dinitrophenylation exclusively in the SC [83] and preferentially led to peripheral tolerance through the generation of Treg memory [84]. Intriguingly, Nrf2 deficiency abrogated hapten sensitization and subsequent immune responses in a hapten-induced mouse model of AD [8]. In this setting, Nrf2 deficiency attenuated the immediate-type contact hypersensitivity response, inflammatory cell (e.g., CD4 + cell, eosinophil, basophil, and mast cell) infiltration, type 2 inflammatory cytokine (e.g., Il4 and Il13) mRNA expression levels, and serum IgE levels [8]. In short, as opposed to the generally accepted anti-inflammatory effect of the KEAP1/NRF2 system, NRF2 can augment cutaneous tissue responses skewed toward a type 2 immunity [8]. Remarkably, Nrf2 deficiency decreased CD4 + and CD8 + T cell proliferation and Treg induction in draining lymph nodes after a single DNFB administration but not DNTB [8]. Taken together, NRF2 may profoundly affect the initiation of tissue-protective inflammatory responses.
It appears that proper activation of NRF2 can ameliorate AD-like skin manifestations and type 2 immunity through its antioxidative and anti-inflammatory effects. In contrast, KEAP1-sensing of epidermal damage can augment innate immune responses and facilitate skin sensitization as a result of increased expression levels of DAMPs, such as IL-1α [8].

NRF2 and Psoriasis
Psoriasis is a chronic recurrent inflammatory skin disease characterized by aberrant hyperproliferation and differentiation of KCs, and immune cell infiltration in the dermis and epidermis [7]. Approximately 125 million people suffer from psoriasis worldwide [85]. Psoriasis has a strong genetic predisposition, and the human leukocyte antigen (HLA)-class 1 allele HLA-C*06:02 is the main risk psoriasis gene [86]. In the pathogenesis of psoriasis, IL-23-mediated activation of the Th17 pathway is regarded as the central inflammatory cascade [87], and biologics, such as TNF-α inhibitors, IL-23 inhibitors, and IL-17 inhibitors, have been used for the treatment of psoriasis [85]. Severe psoriasis can be accompanied by systemic inflammation, which eventually cause cardiovascular comorbidity, namely "psoriatic march" [88]. ROS-mediated oxidative stress is also closely associated with the pathogenesis of psoriasis [89]; therefore, electrophilic agents, such as fumaric acid esters (FAEs), can evoke antioxidative responses and improve psoriasis inflammation [90]. FAEs were first investigated for psoriasis treatment in 1959 [91]. Fumaderm ® (Biogen Inc., Cambridge, MA, USA) is a mixture of DMF and MMF salts. In 1994, Fumaderm ® was approved as a systemic treatment for severe psoriasis, and in 2008, as a systemic treatment for moderate-to-severe psoriasis in Germany [92]. Skilarence ® (Almirall, S.A., Barcelona, Spain) is a novel oral formulation of DMF. In 2017, Skilarence ® was approved by the European Medicines Agency for the treatment of moderate-to-severe plaque psoriasis in Europe [92]. The main clinical effect of FAEs is immunomodulation, wherein NF-κBmediated inflammatory cascades are inhibited [92]. Of note, FAEs exert neuroprotective effects via NRF2 activation in a mouse model of chronic MS (experimental autoimmune encephalomyelitis) [93]. Tecfidera ® (Biogen Inc.) was approved by the Food and Drug Administration and Pharmaceuticals and Medical Devices Agency for relapsing-remitting MS [94], also known as Th17-mediated autoimmune demyelinating disease. Therefore, the therapeutic efficacy of FAEs largely depends on the activation of the KEAP1/NRF2 system. Similar to AD, cumulative evidence has shown that NRF2 can both alleviate and exacerbate psoriasiform dermatitis ( Table 2). Natural compounds or chemical agents that activate NRF2 can ameliorate mouse models of psoriasis. Examples of these agents are described below.

NRF2-Mediated Antioxidative Responses in the Psoriatic Tissues
Previous studies have revealed that expression level of NRF2 in lesional psoriatic skin compared to those in normal control skin are inconsistent between IHC or real-time quantitative polymerase chain reaction analyses [95][96][97]. Lesional psoriatic skin showed lower mRNA expression levels of NRF2 and its downstream targets NQO1, LOR, and FLG than that in non-lesional (perilesional) psoriatic skin [9]. Correspondingly, KEAP1 mRNA expression was decreased in lesional psoriatic skin, compared to that of non-lesional (perilesional) psoriatic skin [98]. Considering that the epidermal thiol gradient is disrupted in psoriatic lesions, it would be natural to assume that the KEAP1-NRF2 system per se is abrogated by psoriasiform tissue reactions. NRF2 has been shown to be upregulated in other experiments examining granulocytes [99] and lymphocytes [100] in peripheral blood mononuclear cells obtained from patients with psoriasis and fibroblasts [101] in psoriatic skin samples. However, it should be noted that blood cells may not reflect the local redox status, and skin biopsy specimens may include both lesional and non-lesional (perilesional) psoriatic skin.
Mouse models of psoriatic skin inflammation that mimic human psoriasis have shown that NRF2 can either be beneficial or detrimental to psoriasis. We have shown that, in an imiquimod (IMQ)-induced mouse model of psoriasis [102], Nrf2 deficiency exacerbated psoriatic skin inflammation and aberrant keratinization by upregulating mRNA expression levels of inflammatory cytokines (i.e., Il6, Tnf, Il23a, and Il17a) and protein expression level of phosphorylated STAT3, and downregulating protein expression levels of epidermal differentiation markers (i.e., K10, FLG, and LOR) [9]. Remarkably, Nrf2 deficiency caused prominent hypogranulosis and parakeratosis [9], the hallmarks of the psoriatic tissue reaction [103]. In contrast to our results, Nrf2 small interfering RNA (siRNA) intervention ameliorated epidermal hyperplasia and reduced protein and mRNA expression levels of stress-induced keratin (i.e., K6, K16, and K17) in this murine model [97]. Yang et al. proposed that NRF2 activation in KCs by inflammatory cytokines (e.g., IL-17 and IL-22) promotes KC proliferation through the upregulation of K6/K16/K17 and releases inflammatory cytokines and chemokines [97]. The actin-related protein 2/3 (Arp2/3) complex, which assembles branched actin filaments, inhibited NRF2 activity and influences epidermal morphogenesis and homeostasis [104]. Consequently, Arp2/3 complex subunit 4 (Arpc4)-knockout mice showed upregulation of NRF2 and developed spontaneous severe psoriasis-like skin inflammation with hyperkeratosis, parakeratosis, and acanthosis [104]. Consistent with this, human psoriatic skin and IMQ-induced psoriatic skin showed decreased ARPC4 protein expression levels through IHC analysis [104]. Van der Kammen et al. suggested that the depletion of the Arp2/3 complex enables NRF2 to enhance the transcription of psoriasis-related genes [104], which may include K6/K16/K17. These phenotypic discrepancies among Nrf2-knockout, Nrf2-siRNA-treated, and Arpc4-knockout mice may be attributed to the difference in the routes of NRF2 intervention (i.e., systemic depletion of NRF2 in Nrf2-knockout mice and local down-or upregulation of NRF2 in Nrf2 siRNA-treated and Arpc4-knockout mice).

NRF2 Activators for In Vitro Models of Psoriasis
The oral hypoglycemic agent metformin is commonly used for the treatment of type 2 diabetes mellitus [105]. Metformin can be beneficial in various skin diseases via its hyperinsulinemic and hyperandrogenic effects [105]. Metformin attenuated the rapidly accelerated fibrosarcoma-1-extracellular signal-regulated kinase 1/2-NRF2 signaling pathway, thereby contributing to intracellular ROS generation and apoptosis in HaCaT cells [106]. Thus, Wang et al. suggested that metformin could be an anti-psoriasis drug that reduces NRF2 expression [106].

Topical NRF2 Activators for Mouse Models of Psoriasis
Topical application of NRF2 activators is effective in IMQ-and 12-O-tetradecanoylphorbol-13-acetate-induced skin inflammation models that mimic human psoriasis. Tussilagonone, a compound derived from the medicinal plant Tussilago farfara L., inhibited activation of the NF-κB and STAT3 signaling pathways in mouse psoriatic skin [107]. Mammalian target of rapamycin (mTOR) is a protein kinase that regulates cell growth, proliferation, and survival [108]. The mTOR inhibitor rapamycin is associated with the regulation of autophagy [109] and the dysfunction of which could contribute to the pathogenesis of psoriasis [110]. Rapamycin restored suppressed autophagy and increased AHR expression by PAH, 2,3,7,8-tetrachlorodibenzo-p-dioxin, in mouse psoriasis skin [111]. Galangin, an active flavonoid extracted from Alpinia officinarum, Alpina galanga, and propolis, downregulated the NF-κB signaling pathway in mouse psoriatic skin [112]. Perillyl alcohol, an essential oil obtained from several plants, such as citrus peel, cherries, and mint, modulated the NF-κB and STAT3 signaling pathways in mouse psoriatic skin [113]. Moringa oleifera L., also known as horseradish tree, suppressed Th17-related cytokines (e.g., IL-23p19, IL-17A, and IL-22) in mouse psoriatic skin [114].

Systemic NRF2 Activators for Mouse Models of Psoriasis
Systemic application of NRF2 activators is also effective in an IMQ-induced mouse model of psoriasis. Astilbin, isolated from a commonly used herbal medicine, reduced ROS accumulation and vascular endothelial growth factor expression in mouse psoriatic skin [115]. Of note, intragastric administration of DMF not only attenuated ear swelling and mRNA expression levels of inflammatory cytokines (i.e., Il6, Tnf, Il23a, and Il17a), but also increased mRNA expression levels of epidermal differentiation markers (i.e., Flg and Lor) in an Nrf2-dependent manner [9]. However, topical application of DMF has not been successful in the treatment of psoriasis, owing to the occurrence of contact dermatitis [116]. This observation suggests that the administration routes of DMF may determine the consequences of the treatment. That is, epidermis-specific NRF2 activation by topical electrophiles may facilitate further skin sensitization [8], while systemic NRF2 activation by oral electrophiles may exert immune modulation [9]. Similarly, topical exposure of TBHQ can cause contact dermatitis [117], whereas TBHQ has been shown to inhibit immune responses [118,119]. Isosorbide DMF (IDMF), a prodrug of DMF, was synthesized to eliminate the skin-sensitizing side effects [120]. IDMF strongly activated NRF2 compared to DMF in vitro and topical application of IDMF ameliorated IMQ-induced psoriatic skin inflammation [120]. Conversely, gallic acid (GA) treatment showed negative effects on NRF2 activation in psoriasis. GA, a natural small molecule found in Radix Paeoniae Rubra, downregulated NRF2 and its targets K16 and K17 in mouse psoriatic skin [121].
Collectively, NRF2 can attenuate psoriatic skin inflammation via antioxidative and antiinflammatory activities but may promote KC proliferation as a consequence of the tissueprotective response. Although DMF has been shown to be a clinically and experimentally effective agent for psoriasis, future applications of NRF2 activators would need more consideration.

Conclusions
It is no doubt that the KEAP1-NRF2 system is dysregulated in the pathogenesis of AD and psoriasis (Figure 1). Because NRF2 plays a prominent role in redox homeostasis, cytoprotection, anti-inflammatory effects, and skin barrier function, considerable efforts have been made to develop NRF2-targeting drugs for AD and psoriasis. The most successful NRF2 activator to date is DMF, which has been demonstrated as a beneficial treatment option for psoriasis and MS, both clinically and experimentally. From a clinical perspective, NRF2 activators and inhibitors have both advantages and disadvantages. As reviewed here, NRF2 may play a dual role in the development of AD and psoriasis. Proper activation of NRF2 can ameliorate AD-like and psoriatic skin inflammation through its antioxidative and anti-inflammatory effects. Conversely, KEAP1-sensing of epidermal damage can lead to the activation of NRF2-mediated tissue-protective responses and exacerbate ADlike and psoriatic skin inflammation by inducing skin sensitization or KCs proliferation. Electrophiles, such as DMF and TBHQ, have shown that the treatment consequence may depend on the activation sites of NRF2. Further mechanistic approaches are necessary for the pharmaceutical applications of the KEAP1-NRF2 system.

Conclusions
It is no doubt that the KEAP1-NRF2 system is dysregulated in the pathogenesis of AD and psoriasis (Figure 1). Because NRF2 plays a prominent role in redox homeostasis, cytoprotection, anti-inflammatory effects, and skin barrier function, considerable efforts have been made to develop NRF2-targeting drugs for AD and psoriasis. The most successful NRF2 activator to date is DMF, which has been demonstrated as a beneficial treatment option for psoriasis and MS, both clinically and experimentally. From a clinical perspective, NRF2 activators and inhibitors have both advantages and disadvantages. As reviewed here, NRF2 may play a dual role in the development of AD and psoriasis. Proper activation of NRF2 can ameliorate AD-like and psoriatic skin inflammation through its antioxidative and anti-inflammatory effects. Conversely, KEAP1-sensing of epidermal damage can lead to the activation of NRF2-mediated tissue-protective responses and exacerbate AD-like and psoriatic skin inflammation by inducing skin sensitization or KCs proliferation. Electrophiles, such as DMF and TBHQ, have shown that the treatment consequence may depend on the activation sites of NRF2. Further mechanistic approaches are necessary for the pharmaceutical applications of the KEAP1-NRF2 system. Figure 1. The KEAP1-NRF2 system in the pathophysiology of atopic dermatitis and psoriasis. NRF2 exerts antioxidative and anti-inflammatory effects, thereby ameliorating IL-4/IL-13 or IL-23/IL-17 axis inflammation and skin manifestations. In contrast, NRF2 can induce tissue-protective responses, which may initiate innate immunity activation or keratinocyte proliferation. AD, atopic dermatitis; IL, interleukin; ILC, innate lymphoid cell; K, keratin; KC, keratinocyte; KEAP1, Kelchlike erythroid cell-derived protein with cap'n'collar homology-associated protein 1; NRF2, nuclear factor erythroid-2-related factor 2; Pso, psoriasis; ROS, reactive oxygen species; Th, helper T.  In contrast, NRF2 can induce tissue-protective responses, which may initiate innate immunity activation or keratinocyte proliferation. AD, atopic dermatitis; IL, interleukin; ILC, innate lymphoid cell; K, keratin; KC, keratinocyte; KEAP1, Kelch-like erythroid cell-derived protein with cap'n'collar homology-associated protein 1; NRF2, nuclear factor erythroid-2-related factor 2; Pso, psoriasis; ROS, reactive oxygen species; Th, helper T.
Author Contributions: T.O., writing-original draft preparation; Y.I., writing-review and editing. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.

Conflicts of Interest:
The authors declare no conflict of interest.