Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans

Abstract

Tapinarof (GSK2894512) is a naturally derived topical treatment with demonstrated efficacy for patients with psoriasis and atopic dermatitis, although the biologic target and mechanism of action had been unknown. We demonstrate that the anti-inflammatory properties of tapinarof are mediated through activation of the aryl hydrocarbon receptor (AhR). We show that tapinarof binds and activates AhR in multiple cell types, including cells of the target tissue-human skin. In addition, tapinarof moderates proinflammatory cytokine expression in stimulated peripheral blood CD4+ T cells and ex vivo human skin, and impacts barrier gene expression in primary human keratinocytes; both of these processes are likely to be downstream of AhR activation based on current evidence. That the anti-inflammatory properties of tapinarof derive from AhR agonism is conclusively demonstrated using the mouse model of imiquimod-induced psoriasiform skin lesions. Topical treatment of AhR-sufficient mice with tapinarof leads to compound-driven reductions in erythema, epidermal thickening, and tissue cytokine levels. In contrast, tapinarof has no impact on imiquimod-induced skin inflammation in AhR-deficient mice. In summary, these studies identify tapinarof as an AhR agonist and confirm that its efficacy is dependent on AhR.

<b><i>Staphylococcus epidermidis</i></b> Activates Aryl Hydrocarbon Receptor Signaling in Human Keratinocytes: Implications for Cutaneous Defense

“…For example, functional AhR seems to be required for normal keratinocyte differentiation [17] and for mouse skin barrier integrity [18]. Moreover, activation of the AhR has been reported to dampen skin inflammation in psoriasis [19,20] and to improve the skin barrier in atopic dermatitis [21]. Whereas these reports illustrate an important role of the AhR in cutaneous barrier homeostasis, the role of the AhR in cutaneous innate defense is less understood.…”

Topische Therapie bei Psoriasis vulgaris - ein Behandlungspfad

“…Neue topische Substanzen befinden sich in der Pipeline, hier seien nur drei genannt: Eine Phase-II-Studie mit Tapiranof Creme 1% (Aryl-Hydrocarbon-Rezeptor-Agonist, reguliert Zytokine wie IL-17 und IL-22) [4] wurde auf der AAD 2019 präsentiert und zeigte PASI 90-Raten um 40% bei guter Verträglichkeit [5]. Tofacitinib, ein JAK-Inhibitor, oral zur Therapie der Psoriasis-Arthritis zugelassen, zeigte bei topischer Anwendung in zwei Studien eine gute Wirksamkeit, eine weitere Phase-II-Studie konnte dies aber nicht bestätigen [6].…”

Aryl Hydrocarbon Receptor Activation: From Coal to Dioxin

“…Tapinarof is a AHR agonist with clinical efficacy for AD and psoriasis patients, reducing erythema, epidermal thickening, and tissue cytokine levels (7,8,9). Tapinarof reduces IL-17A levels, which is a key player in psoriasis.…”

“…Moreover, tapinarof also demonstrates efficacy in AD, which is largely driven by Th2 cytokines (8). While AHR activation may be driving tapinarof's efficacy in psoriasis and AD, tapinarof also has antioxidant properties that may derive from Nrf2 pathway activation (9). NrF2 is a leucine zipper protein that regulates antioxidant proteins which protect against oxidative damage triggered by injury and inflammation.…”