AhR agonism by tapinarof regulates TH2 and TH17 cell function in human skin
EXPERIMENTAL DERMATOLOGY(2024)
Abstract
The aryl hydrocarbon receptor (AhR) is a transcription factor for skin homeostasis and barrier function. Tapinarof, a topical AhR agonist, has shown impressive clinical efficacy in psoriasis (PSO) and atopic dermatitis (AD), inducing long-lasting remissions. However, tapinarof's anti-inflammatory mechanism remains unclear. We aimed to investigate tapinarof's effects on T cells in healthy skin, AD, PSO, and allergic contact dermatitis (ACD). Using a short-term human skin explant model, we cultured skin biopsies from PSO, AD and ACD with tapinarof for 24 hours. We observed elevated cytokine levels in disease-driving populations of tissue-resident T cells (TRM) (IL-13+CD4+ TRM in AD and IL-17a+CD8+ TRM in PSO), validating our model. Tapinarof significantly reduced IL-13 and IL-17a in the respective diseases and populations. In ACD, tapinarof decreased IL-13 levels in TRM and CD4+ T cells without affecting IFN-γ expression. By single-cell RNA-sequencing of T cells isolated from tapinarof-treated AD and PSO biopsies, we found that these cells displayed significant metabolic impairments. These findings were corroborated by transcriptomic analysis of tapinarof-treated PBMCs and CD4+ memory T cells, which interestingly showed a strong concerted downregulation of fatty-acid beta-oxidation and cholesterol metabolism. Mechanistic studies confirmed that glycolysis and oxidative phosphorylation were reduced in resting and activated memory T cells after tapinarof treatment. Strikingly, basal respiration was significantly impaired in both resting and activated memory T cells, whereas basal glycolysis was only affected after activation. Since memory T cells rely heavily on oxidative phosphorylation for energy production, treating memory T cells with tapinarof could lead to a metabolic impairment. In summary, our ex vivo model demonstrates that treatment with tapinarof significantly reduces disease-relevant cytokines in skin T cells from AD,PSO and ACD biopsies. Furthermore, we provide mechanistic evidence that this is mediated by impairment of glycolysis and oxidative phosphorylation, revealing a previously unknown mechanism of action.
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Key words
th17 cell function,tapinarof,th2,human skin
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