Oxidative Stress in Atopic Dermatitis and Possible Biomarkers: Present and Future

Abstract

Oxidative stress is important in the pathogenesis of atopic dermatitis (AD); it can damage keratinocytes, increase dermal inflammation, and reduce skin barrier function, the hallmarks of atopic dermatitis pathogenesis. Measuring oxidative stress is possible by identifying peripheral markers, which could have a predictive value of disease severity, disease progression and response to therapy, with a potentially significant impact on patient management. Our review explored this fascinating field of research, focusing on old and new possible biomarkers that may represent an effective tool to investigate the inflammatory-oxidative axis in AD, adding clinically important information to patient care.

Oxidative Stress and Inflammation

A crucial moment of the inflammatory process is the infiltration of inflammatory cells into the site of insult. These activated cells release many inflammatory mediators and reactive species, inducing tissue damage and oxidative stress.[1] Inflammation and oxidative stress are interrelated:[1] Inflammatory cells release several oxidants at the site of inflammation, contributing to oxidative imbalance; and vice versa, oxidants promote the activation of specific intracellular redox signalling, which enhances proinflammatory factors gene production.[2] The interdependent relationship between inflammation and oxidative stress has been supported by numerous studies. Oxidative stress can induce inflammation through activation of multiple pathways, such as the transcription factor NF-κB and the NOD-like receptor protein 3 (NLRP3) inflammasome.[3,4] Moreover, direct DNA modification induced by reactive oxygen species (ROS) is an additional important cause of the inflammatory cascade initiation, with consequent activation of innate immunity. Furthermore, oxidative stress induces the alteration of extracellular components, such as cysteine (Cys) in disulfide cystine (CySS), able to promote monocyte adhesion to vascular endothelial cells. Moreover, oxidative stress activates NF-κB signalling and increases the expression of proinflammatory cytokines.[5] The identification of the primary abnormality, if oxidative stress accentuates inflammation or vice versa, is not easy, even if it could be of great clinical importance.

Oxidative Stress in Atopic Dermatitis Immuno-Pathogenesis

Atopic dermatitis (AD) is a chronic-relapsing skin disease whose prevalence continuously increases. The pathogenesis of AD is very complex and still poorly understood. It is characterised by an interaction among genetic, immunological and environmental aspects. In addition to genetic predisposition, development and maintenance of AD are associated with environmental triggers, skin barrier defects, immune dysregulation and hypersensitivity.[6] Recently, oxidative stress has also been implicated in the pathogenesis of AD. Indeed, it has been reported the presence of oxidative imbalance in AD, especially during AD exacerbation, with an increase of oxidative activity and a decreased action of antioxidant systems.[7,8] Oxidative stress in AD patients has been evaluated through many urinary and serum biomarkers [Table 1]. A recent review reported the data from 33 published studies on the most frequently investigated biomarkers of oxidative stress in AD, highlighting the important role of this aspect in AD immunopathogenesis and the need for additional future studies with standardised measurement methods of these biomarkers.[9] In particular, 8-hydroxydeoxyguanosine (8-OHdG), nitrite/nitrate and selenium are altered in the urine of children with AD, and a marked increase is particularly appreciated during disease exacerbation or patient hospitalisation.[10] Indeed, these markers positively correlate with the severity of cutaneous manifestations.[11] More recently, two case–control studies have demonstrated that patients with atopic eczema have a significantly higher level of serum malondialdehyde (MDA), a marker of lipid peroxidation and lower levels of vitamins A, C and E, with antioxidants functions, for controls.[8,12] Interestingly, it has been shown in mice models and in AD patients that the antioxidant factor heme oxygenase 1 was able to mitigate the development of AD manifestations.[8]

Table 1.

Biomarkers of oxidative stress in atopic dermatitis

Study population	Serum biomarker	Urinary biomarker	Reference
Children		8-OHdG	[13,14]
Children		nitrite/nitrate	[15]
Children		selenium	[16]
Adult	MDA		[17,18]
Adult		biopyrrins	[23]

8-OHdG=8-deoxyguanosine, MDA=Malondialdehyde

The most commonly investigated samples were blood and urine. Skin biopsy or cutaneous components are rarely used. In two cases, cord blood was used; in the other cases, placenta, cutaneous microdialysis, exhaled breath condensates, and ocular brush cytology were analysed.[9] In skin samples, oxidative stress was evaluated through lipid peroxidation, as well as the generation of free radicals (including superoxide anion radicals, hydroxyl radicals, and peroxide radicals), peroxidation resistance of the substrate, and activity of the antioxidant defense system.[9] Other studies revealed that the mediating immunohistochemical technique elevated levels of dinitrophenol and biopyrrins in a skin biopsy from AD patients with respect to controls.[9] Several environmental, physical and psychological factors could be sources of oxidative stress in AD. Air pollutants, tobacco smoke, volatile organic compounds, and particulate matter represent risk factors for AD, or they can aggravate the dermatitis.[8] Those factors induce oxidative stress in the skin, contributing to cutaneous barrier dysfunction, inflammation and immune dysregulation. Song et al.[13] reported that children with AD exposed to short-term ultrafine particles had elevated levels of urine 8-OHdG, a DNA oxidation marker. In recent years, more attention has been given to this theme, focusing on the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator (AhR/ARNT) signalling system. It plays a crucial role in keratinocyte homeostasis, promoting oxidative balance in a ligand-dependent manner. Environmental pollutants bind to AhR and induce skin inflammation via ROS production and DNA damage. The pathogenic implication of AhR in AD has been recently studied: clinical trials have demonstrated therapeutic benefits in AD of topical tapinarof. Tapinarof is a high-affinity AhR ligand with antioxidative activity via a ROS-scavenging structure.[15] On the other hand, skin microbes might be another important source of oxidative stress, and their role in AD inflammation has been well established.[8] The altered resident flora in AD patients stimulates IL-4 and IgE synthesis to cause dermal inflammation and, therefore, itching and scratching in a vicious circle. A third environmental factor that contributes to oxidative damage may be psychological stress. There is evidence that psychological stress enhances oxidative processes by having pro-oxidant characteristics. Research indicates that psychological stress may enhance the potential of oxidative stress-induced disease by inhibiting apoptosis in human blood cells and decreasing DNA repair.[16] The hallmarks of AD are dermal inflammation and skin barrier defects. Both might be influenced by redox imbalance. Oxidative stress actives NF-κB pathway, which induces the release of proinflammatory mediators, including IL-33, IL-6 and IL-8, that in turn support dermal inflammation.[8,17,18] Studies in animal models have demonstrated that oxidative stress has an important role in AD development and worsening by enhancing Th2 immune response polarisation.[14,19] Moreover, oxidative stress contributes to skin barrier damage, causing intracellular changes direct to DNA, cellular enzymes and cell membrane structures. Many studies have reported how ROS, achieved from environmental pollutants and ultraviolet radiation, generate oxidative protein damage, lipid peroxidation, modification, translocation and degradation of scavengers, resulting in skin barrier dysfunction and aggravation of AD.[20] Furthermore, an impaired skin barrier aids microbial skin colonization and penetration, leading to increased IgE sensitization.[21] The impact of ROS on DNA, lipids and proteins can be evaluated through different biomarkers. Urinary 8-OHdG is a biomarker of oxidative DNA damage, while biomarkers of lipid peroxidation are MDA, NO, and 4-hydroxy-2-nonenal (HNE). Protein oxidation could be assessed by advanced oxidation protein products and advanced glycation end-product levels. The clinical value of these products in AD is controversial. In addition, none of the previous studies have investigated if oxidative biomarkers correlate with the severity of skin inflammation and if they might have a prognostic function of response to systemic therapies.

Novel Possible Biomarker: Urinary Biopyrrins and AD

Among the human biological redox defence systems, bilirubin is one of the most potent, for its strong antioxidant and protective actions. The redox imbalance and increased levels of ROS are responsible for bilirubin oxidation. The bilirubin oxidative metabolites are biopyrrins. The biopyrrins are rapidly excreted into urine. The increased oxidation of bilirubin correlates with an increased urinary biopyrrins (UBP) level. Then, the UBP level represents an oxidative stress biomarker.[22,23] It has been reported that UBP levels could be modified by various types of stress, including psychological/social stress and somatic diseases, such as psoriasis.[22] and AD.[23] Recently, more attention has been paid to the intricate relationship between oxidative stress and atopic diseases. Interestingly, recent research studies have investigated the possible involvement of biopyrrins in AD pathogenesis, showing augmented urinary levels with respect to healthy controls.[23] However, the correlation of UBP with the severity and phenotype of cutaneous disease has not yet been investigated. Urinary biopyrrins might represent a “real-time” biomarker of the redox state in AD patients as well as a useful predicting tool for the risk of CV diseases, adding clinically important information to patient care.

Conclusion and Future Perspectives

A major challenge in monitoring oxidative stress in biological systems is the highly reactive nature of ROS and their compounds. Consequently, considerable effort has been directed to evaluate their downstream products, which can provide indirect evidence of ROS action. It is controversial whether antioxidants may manage AD. A systematic review and meta-analysis have been performed to assess the effectiveness and safety of antioxidant therapy in AD.[24] Antioxidants were often linked to statistically significant decreases in disease severity (p 0.0001) but not to itch score (P = 0.59). There were no significant adverse effects noted. Independent of baseline disease severity and length of therapy, subgroup analysis showed that antioxidants were linked to a substantial decline in severity score (p 0.05). Antioxidants, however, provided additional benefits only to children (P = 0.02) and not to adults (P = 0.30). Vitamin D, vitamin D and E combined, vitamin A, vitamin D and vitamin E combined, and topical vitamin B12 treatment all significantly reduced the severity score (p 0.05). Studies were significantly heterogeneous (I2 = 50%; P = 0.003). After eliminating study heterogeneity sources, the effect estimates did not significantly change. This meta-analysis reveals that antioxidants may be a safe and efficient treatment for AD patients, particularly in children, when combined with oral vitamin D and topical vitamin B12.

The monitoring and managing redox imbalance in AD patients could be important to prevent comorbidities. The emergence of metabolic comorbidities such as hyperlipidaemia, hypertension and enhanced glucose intolerance, all resulting in metabolic syndrome, is significantly influenced by inflammation and oxidative stress. According to numerous studies, the risk for metabolic syndrome can be reduced considerably by losing weight and concentrating interventions on dietary changes like time-restricted eating, special diets like the Mediterranean diet, increasing physical activity, changing sleep patterns, or even lowering stress. In metabolic syndrome, ROS promote mitochondrial dysfunction, protein degradation, lipid peroxidation and reduce antioxidant function.[25]

The identification of peripheral markers with possible predictive value of disease severity, disease progression and response to therapy could potentially influence the AD patient care management.

Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest.