Th158 - The AhR Agonist Tapinarof Suppresses Human Skin Inflammation by Inducing Metabolic Reprogramming and Reducing Production of Mitochondrial Pro-inflammatory DAMPs

Abstract Text: The topical AhR agonist tapinarof effectively treats both psoriasis and atopic dermatitis but there are no mechanistic studies of its effects in human skin. We treated inflamed human skin grafts carried by NSG mice for 3 weeks with topical tapinarof versus vehicle control. Tapinarof reduced T cell, macrophage, DC and NK cell activation. Upstream DAMP sensing via cytoplasmic nucleic acid sensing was reduced, leading to reduced cGAS/STING, and inflammasome activation, decreased type I, II, and III IFN and type 1, type 2 and type 17 cytokine production. In vitro, in human T cells, tapinarof reduced mitochondrial ROS production and release of mtDNA into the cytoplasm, impairing type I IFN signaling and reducing T cell activation and proliferation. Treatment of psoriatic skin constructs led to metabolic reprogramming, including inhibition of hypoxia sensing, glycolysis, fatty-acid (FA) b-oxidation, and glutamate influx. Tapinarof-induced AhR signaling reduced HIF1α and mTOR expression in T cells, limiting glucose uptake, glycolytic capacity, and FA metabolism, while also impairing mitochondrial respiration and ATP production, producing marked metabolic dysfunction. Finally, tapinarof disrupted mitochondrial function, by reduced mitochondrial membrane potential and mitochondrial mass, suggesting a decrease in mitochondrial fitness. In summary, tapinarof acts at the level of the mitochondria to reduce DAMP sensing via reduced ROS production and mtDNA release, thus markedly reducing inflammatory tone, and by blocking multiple metabolic pathways and impairing mitochondrial function, thus blocking the cells' ability to use and generate energy in the hypoxic skin microenvironment.