Acta Dermato-Venereologica 98-10CompleteContent

918 REVIEW ARTICLE Antioxidative Phytochemicals Accelerate Epidermal Terminal Differentiation via the AHR-OVOL1 Pathway: Implications for Atopic Dermatitis Masutaka FURUE 1–3 , Akiko HASHIMOTO-HACHIYA 1 and Gaku TSUJI 1 1 Department of Dermatology, 2 Research and Clinical Center for Yusho and Dioxin, and 3 Division of Skin Surface Sensing, Department of Dermatology, Kyushu University, Fukuoka, Japan Aryl hydrocarbon receptor (AHR) is a chemical sensor that is expressed abundantly in epidermal keratino- cytes. Oxidative AHR ligands induce the production of reactive oxygen species. However, antioxidant AHR li- gands inhibit reactive oxygen species generation via activation of nuclear factor-erythroid 2-related fac- tor-2, which is a master switch for antioxidative signal- ling. In addition, AHR signalling accelerates epidermal terminal differentiation, but excessive acceleration by oxidative ligands, such as dioxins, may induce chlo- racne and inflammation. However, antioxidative phy- tochemical ligands induce the beneficial acceleration of epidermal differentiation that repairs skin barrier disruption. The upregulated expression of differentia- tion molecules, such as filaggrin, is mediated via the AHR-OVOL1 axis. This AHR-OVOL1 system is capable of counteracting skin barrier dysfunction in T-helper type 2-shifted inflammation. This article reviews the dynamic and multifaceted role of AHR in epidermal biology and discusses the potential use of antioxidati- ve phytochemical ligands for AHR in inflammatory skin diseases, such as atopic dermatitis. Key words: antioxidative phytochemicals; filaggrin; aryl hydro- carbon receptor; nuclear factor-erythroid 2-related factor-2; OVOL1; atopic dermatitis. Accepted Jul 3, 2018; Epub ahead of print Jul 4, 2018 Acta Derm Venereol 2018; 98: 918–923. Corr: Masutaka Furue, Department of Dermatology, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: furue@ dermatol.med.kyushu-u.ac.jp A topic dermatitis (AD) is characterized by chronic itch, cutaneous inflammation and dry skin with epidermal barrier dysfunction (1–3). Since the discovery of T-helper type 1 (TH1) and TH2 immune regulation by Mosmann et al. (4), the TH2-polarized immune response has been thought to be a cardinal driver in allergic di- seases including AD (5–9). This notion has been proven because blockade of TH2-derived interleukin (IL)-4 and IL-13 signalling by a specific anti-IL-4 receptor antibody, dupilumab, successfully improves skin inflammation in patients with AD (10–12). In addition, TH2-derived IL- 31 is a potent itching-scratching inducer, and the admi- nistration of anti-IL-31 receptor antibody, nemolizumab, improves atopic itching in patients with AD (13–16). doi: 10.2340/00015555-3003 Acta Derm Venereol 2018; 98: 918–923 SIGNIFICANCE Aryl hydrocarbon receptor (AHR) is a chemical sensor ac- tivated by external and internal ligands. Oxidative AHR li- gands induce the production of reactive oxygen species. However, antioxidative phytochemical AHR ligands inhibit ROS generation via activation of nuclear factor-erythroid 2-related factor-2, which is a master switch for antiox- idative signalling. In addition, AHR signalling upregulates filaggrin expression via OVOL1 transcription factor and accelerates epidermal terminal differentiation. This AHR- OVOL1 system is capable of counteracting the skin barrier dysfunction in T helper type 2-shifted inflammation. The- refore, antioxidative phytochemicals targeting AHR are po- tentially beneficial for barrier-disrupted skin diseases, such as atopic dermatitis. Genome-wide association studies in different ethnici- ties have revealed at least 19 susceptible genes, including filaggrin (FLG), OVO-like 1 (OVOL1) and IL4/IL13 (17–22). AD exhibits heterogeneous clinical and labora- tory manifestations influenced by genetic, environmental and social factors (2, 5, 23–26). However, xerosis or dry skin due to skin barrier disruption is the most frequent clinical sign in AD (23, 25). Skin barrier maturation is accomplished by sequential and coordinated expression of various terminal diffe- rentiation proteins, such as FLG and loricrin (LOR) (27). In accordance, FLG and LOR expression levels have been reported to be reduced in lesioned and non- lesioned skin in AD (28–30). Loss-of-function mutations of FLG have been demonstrated in some patients with AD, ranging from 10% to 50% in the Northern European and Asian AD population (31–34). Ichthyosis vulgaris is also known to be caused by the loss-of function mutation of FLG (35). This may explain why AD is significantly comorbid with ichthyosis vulgaris (25, 31). However, FLG mutations are not found in all patients with AD, and they are less common in Southern Europeans (36) and are even absent in some African countries (37, 38). A humid atmosphere may reduce the contribution of FLG mutations to the onset of AD (39). Of note, TH2-derived cytokines, IL-4 and IL-13, inhibit FLG and LOR expression (29, 30, 40–42). IL- 31 also downregulates FLG and LOR expression (43). This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2018 Acta Dermato-Venereologica.

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