Yoko Kuba‐Fuyuno

Cutaneous lupus erythematosus (CLE) is an autoimmune disease in which type I interferon (IFN) has been well-established as a central pathogenic factor. It presents with diverse cutaneous manifestations that markedly impair patients’ quality of life. Therapeutic options for CLE remain limited and are often insufficient, highlighting the need for novel treatment strategies. The aryl hydrocarbon receptor (AHR) is a transcription factor that modulates immune responses and has recently attracted attention as a potential therapeutic target for autoimmune diseases. We previously confirmed that treatment of normal human epidermal keratinocytes with IFNα and Poly I:C upregulated the expression of the CLE-like inflammatory cytokines IFNκ, CXCL10, and IL6, as well as the B-cell activating factor. In the present study, we demonstrated by quantitative PCR and Western blotting that pretreatment with the AHR agonist tapinarof suppressed the upregulation of IFNκ and CXCL10. Mechanistically, we demonstrated that tapinarof suppresses IFNκ expression by inhibiting STAT1 phosphorylation in an AHR-dependent manner, thereby attenuating the nuclear translocation of ISGF3. Overall, we show that tapinarof suppresses CLE-like inflammation in human keratinocytes in an AHR-dependent manner, suggesting that it may represent a novel therapeutic agent for CLE.

Atopic dermatitis (AD) is a chronic inflammatory dermatitis underpinned by Type 2 inflammation driven by cytokines such as IL‐4 and IL‐13. It is characterized by skin barrier dysfunction, Th2 immune deviation, and pruritus. While biologics and oral Janus kinase (JAK) inhibitors demonstrate high therapeutic efficacy by targeting cytokines that exert their effects via the JAK, specifically IL‐4, IL‐13, and IL‐31, comprehensive disease control requires additional approaches that modulate JAK‐independent pathways. Factors such as TNF‐α, IL‐25, IL‐33, microbial antigens, and physical stimuli activate mitogen‐activated protein kinase and nuclear factor‐κB signaling in a JAK‐independent manner, sustaining the disease activity. Consequently, in some cases, a strategy incorporating topical treatment that inhibits JAK‐independent pathways is indispensable alongside systemic treatment. One potential strategy of this kind involves the aryl hydrocarbon receptor (AhR), ligand‐activated transcription factor. Under Th2‐polarized conditions, the expression of indoleamine 2,3‐dioxygenase 1 (IDO1) is downregulated, limiting the availability of tryptophan‐derived metabolites. This scarcity of endogenous AhR ligands subsequently compromises physiological AhR signaling. Tapinarof, a therapeutic AhR‐modulating agent (TAMA), activates AhR without generating excessive reactive oxygen species. This exerts multiple effects: enhancing antioxidant defenses via nuclear factor erythroid 2‐related factor 2 (NRF2) activation, restoring barrier dysfunction, suppressing Th2 inflammation, and correcting abnormalities associated with pruritus‐related molecules. Furthermore, clinical trials of tapinarof have demonstrated improvement of the disease activity and pruritus, with efficacy intensifying over long‐term treatment. Although adverse events such as folliculitis, acne, contact dermatitis, and headache occur, they are generally manageable by adjusting the frequency of application based on their reversibility and time of onset. Moreover, considering potential antagonism by IL‐24 induced by tapinarof, combining tapinarof with systemic agents, topical therapies, or phototherapy may serve to optimize the therapeutic effects. In conclusion, AhR functions as a molecular hub integrating AD pathology, and the TAMA tapinarof expands therapeutic strategies in the treatment of AD.

Enfortumab vedotin (EV), targeting Nectin‐4, is effective in advanced urothelial carcinoma but frequently causes skin toxicities. This study examined the possible contribution of prior immune checkpoint inhibitor (ICI) therapy and higher EV doses to EV‐related skin toxicity (EVST) development. Histopathological findings suggested both direct keratinocyte damage and immune‐mediated mechanisms. These insights may improve clinical management of EVST.

Atopic dermatitis (AD) is characterized by chronic inflammation, barrier dysfunction, and pruritus, exacerbated by external stimuli, such as scratching. This study investigates the role of extracellular adenosine triphosphate (ATP) in the pathophysiology of AD and assesses the therapeutic potential of clodronate, an ATP release inhibitor. Our research demonstrates that extracellular ATP impairs skin barrier function by reducing the filaggrin expression in the keratinocytes, a critical protein for barrier integrity. Furthermore, ATP release, triggered by IL-4 and mechanical stimuli, amplifies inflammation by promoting cytokine and chemokine production by the immune cells. Clodronate, by inhibiting ATP release, restores the filaggrin levels in the keratinocytes, reduces TARC production in the dendritic cells, and alleviates AD symptoms in a mouse model. These findings suggest that targeting extracellular ATP could offer a novel therapeutic approach to improving skin barrier function and reducing inflammation in AD. Future studies should explore the long-term efficacy and safety of ATP-targeted therapies in clinical settings.

Chloracne is the major skin symptom caused by dioxin intoxication. Dioxin activates the aryl hydrocarbon receptor (AHR)–cytochrome p450 1A1 (CYP1A1) system, generates oxidative stress, and induces hyperkeratinization of keratinocytes and sebocytes leading to chloracne. Nuclear factor-erythroid 2-related factor-2 (NRF2) is a master switch that induces the expression of various antioxidative enzymes, such as heme oxygenase-1. Cinnamaldehyde is an antioxidant phytochemical that inhibits AHR–CYP1A1 signaling and activates the NRF2–antioxidative axis. The cinnamaldehyde-containing Kampo herbal medicine Keishibukuryogan is capable of improving chloracne in Yusho patients who are highly contaminated with dioxin. Agents with dual functions in promoting AHR–CYP1A1 inhibition and NRF2 activation may be useful for managing dioxin-related health hazards.

[This corrects the article DOI: 10.1155/2018/9524657.].

The skin covers the outer surface of the body, so the epidermal keratinocytes within it are susceptible to reactive oxygen species (ROS) generated by environmental pollutants such as benzo(a)pyrene (BaP), a potent activator of aryl hydrocarbon receptor (AHR). Antioxidant activity is generally mediated by the nuclear factor‐erythroid 2‐related factor‐2 (NRF2) and heme oxygenase‐1 (HO1) axis in human keratinocytes. Perillaldehyde is the main component of Perilla frutescens, which is a medicinal antioxidant herb traditionally consumed in East Asia. However, the effect of perillaldehyde on the AHR/ROS and/or NRF2/HO1 pathways remains unknown. In human keratinocytes, we found that perillaldehyde (1) inhibited BaP‐induced AHR activation and ROS production, (2) inhibited BaP/AHR‐mediated release of the CCL2 chemokine, and (3) activated the NRF2/HO1 antioxidant pathway. Perillaldehyde is thus potentially useful for managing inflammatory skin diseases or disorders related to oxidative stress.