Excessive Production of Hydrogen Peroxide in Mitochondria Contributes to Atopic Dermatitis.

Atopic dermatitis (AD) is a complex disease characterized by chronic recurring eczema and pruritus. In addition, patients with AD display increased cutaneous and systemic levels of oxidative damage markers, whose source remains elusive. In this study, we investigated oxidative and mitochondrial stress in AD epidermis. The levels of superoxide dismutase 2 and hydrogen peroxide are augmented in the mitochondria of flaky tail (ft/ft) mouse keratinocytes, which is associated with the inhibition of the glutathione system and catalase. Furthermore, reduced levels of glutathione peroxidase 4 are associated with accumulation of malondialdehyde, 4-hydroxy-2-nonenal, and oxidized phosphatidylcholines in ft/ft epidermis. Cytochrome c is markedly increased in ft/ft epidermis, hence showing mitochondrial stress. Topical application of MitoQ, which is a mitochondrial-targeting antioxidant, to ft/ft mouse skin reduced damage to macromolecules and inflammation and restored epidermal homeostasis. Absence of alteration in the expression of superoxide dismutase 2, catalase, and glutathione peroxidase 4 and limited lipid peroxidation as well as oxidized phosphatidylcholines in the epidermis of Flg-/- mice suggest that FLG deficiency marginally contributes to oxidative stress in ft/ft epidermis. Increased superoxide dismutase 2, lipid peroxidation, and cytochrome c in the epidermis of patients with AD, associated with reduced antioxidant response in primary AD keratinocytes, corroborate mitochondrial dysfunction and lack of cellular adjustment to oxidative stress in AD epidermis.

Mitochondrial Activity Is Upregulated in Nonlesional Atopic Dermatitis and Amenable to Therapeutic Intervention.

Previous work has shown increased expression of genes related to oxidative stress in nonlesional atopic dermatitis (ADNL) skin. Although mitochondria are key regulators of ROS production, their function in AD has never been investigated. Energy metabolism and the oxidative stress response were studied in keratinocytes (KCs) from patients with ADNL or healthy controls. Moreover, ADNL human epidermal equivalents were treated with tigecycline or MitoQ. We found that pyruvate and glucose were used as energy substrates by ADNL KCs. Increased mitochondrial oxidation of (very) long-chain fatty acids, associated with enhanced complexes I and II activities, was observed in ADNL KCs. Metabolomic analysis revealed increased tricarboxylic acid cycle turnover. Increased aerobic metabolism generated oxidative stress in ADNL KCs. ADNL human epidermal equivalents displayed increased mitochondrial function and an enhanced oxidative stress response compared with controls. Treatment of ADNL human epidermal equivalents with tigecycline or MitoQ largely corrected the AD profile, including high p-65 NF-κB, abnormal lamellar bodies, and cellular damage. Furthermore, we found that glycolysis supports but does not supersede mitochondrial metabolism in ADNL KCs. Thus, aerobic metabolism predominates in ADNL but leads to oxidative stress. Therefore, mitochondria could be a reservoir of potential therapeutic targets in atopic dermatitis.

Peroxisomal Fatty Acid Oxidation and Glycolysis Are Triggered in Mouse Models of Lesional Atopic Dermatitis.

Alterations of the lipid profile of the stratum corneum have an important role in the pathogenesis of atopic dermatitis (AD) because they contribute to epidermal barrier impairment. However, they have not previously been envisioned as a cellular response to altered metabolic requirements in AD epidermis. In this study, we report that the lipid composition in the epidermis of flaky tail, that is, ft/ft mice mimics that of human lesional AD (ADL) epidermis, both showing a shift toward shorter lipid species. The amounts of C24 and C26 free fatty acids and C24 and C26 ceramides-oxidized exclusively in peroxisomes-were reduced in the epidermis of ft/ft mice despite increased lipid synthesis, similar to that seen in human ADL edpidermis. Increased ACOX1 protein and activity in granular keratinocytes of ft/ft epidermis, altered lipid profile in human epidermal equivalents overexpressing ACOX1, and increased ACOX1 immunostaining in skin biopsies from patients with ADL suggest that peroxisomal ß-oxidation significantly contributes to lipid signature in ADL epidermis. Moreover, we show that increased anaerobic glycolysis in ft/ft mouse epidermis is essential for keratinocyte proliferation and adenosine triphosphate synthesis but does not contribute to local inflammation. Thus, this work evidenced a metabolic shift toward enhanced peroxisomal ß-oxidation and anaerobic glycolysis in ADL epidermis.

PPARdelta in Affected Atopic Dermatitis and Psoriasis: A Possible Role in Metabolic Reprograming.

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors expressed in the skin. Three PPAR isotypes, α (NRC1C1), ß or δ (NRC1C2) and γ (NRC1C3), have been identified. After activation through ligand binding, PPARs heterodimerize with the 9-cis-retinoic acid receptor (RXR), another nuclear hormone receptor, to bind to specific PPAR-responsive elements in regulatory regions of target genes mainly involved in organogenesis, cell proliferation, cell differentiation, inflammation and metabolism of lipids or carbohydrates. Endogenous PPAR ligands are fatty acids and fatty acid metabolites. In past years, much emphasis has been given to PPARα and γ in skin diseases. PPARß/δ is the least studied PPAR family member in the skin despite its key role in several important pathways regulating inflammation, keratinocyte proliferation and differentiation, metabolism and the oxidative stress response. This review focuses on the role of PPARß/δ in keratinocytes and its involvement in psoriasis and atopic dermatitis. Moreover, the relevance of targeting PPARß/δ to alleviate skin inflammation is discussed.

Xenobiotic Receptors and Their Mates in Atopic Dermatitis.

Atopic dermatitis (AD) is the most common inflammatory skin disease worldwide. It is a chronic, relapsing and pruritic skin disorder which results from epidermal barrier abnormalities and immune dysregulation, both modulated by environmental factors. AD is strongly associated with asthma and allergic rhinitis in the so-called 'atopic march.' Xenobiotic receptors and their mates are ligand-activated transcription factors expressed in the skin where they control cellular detoxification pathways. Moreover, they regulate the expression of genes in pathways involved in AD in epithelial cells and immune cells. Activation or overexpression of xenobiotic receptors in the skin can be deleterious or beneficial, depending on context, ligand and activation duration. Moreover, their impact on skin might be amplified by crosstalk among xenobiotic receptors and their mates. Because they are activated by a broad range of endogenous molecules, drugs and pollutants owing to their promiscuous ligand affinity, they have recently crystalized the attention of researchers, including in dermatology and especially in the AD field. This review examines the putative roles of these receptors in AD by critically evaluating the conditions under which the proteins and their ligands have been studied. This information should provide new insights into AD pathogenesis and ways to develop new therapeutic interventions.