D3.232 - The AhR agonist tapinarof suppresses human skin inflammation by inducing metabolic reprogramming and reducing production of mitochondrial pro-inflammatory DAMPs

The topical aryl hydrocarbon receptor (AhR) agonist tapinarof effectively treats psoriasis and atopic dermatitis, but its mechanism of action in human skin remains poorly defined.

Inflamed human skin xenografts were generated by grafting healthy skin onto NOD scid gamma (NSG) mice followed by allogeneic peripheral blood mononuclear cell (PBMC) transfer. Grafts were treated topically for 3 weeks with tapinarof or vehicle and analyzed by histology, immunostaining and bulk RNA sequencing. Mechanistic assays were performed in activated human T cells and 3D psoriatic skin constructs.

Tapinarof treatment significantly reduced epidermal thickness and skin immune cell infiltration. It suppressed activation of T cells, macrophages, dendritic cells and natural killer (NK) cells. Cytosolic nucleic acid sensing and damage-associated molecular pattern (DAMP) pathways were downregulated, with reduced cGAS/STING signaling and inflammasome activation, and decreased interferon (IFN) responses and type 1, type 2 and type 17 cytokine production. In vitro, in activated human T cells, tapinarof reduced mitochondrial reactive oxygen species (ROS) production and mitochondrial DNA (mtDNA) release into the cytoplasm, thereby 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) β-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, inducing marked metabolic dysfunction. 

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, thus blocking the cells' ability to use and generate energy in the hypoxic skin microenvironment.