1101 Tapinarof, a therapeutic AHR-modulating agent, induces semaphorin 3A production via NRF2 in human keratinocytes: Implications for atopic dermatitis

Semaphoring 3A (Sema3A) is a secreted protein, which involved in repulsive axon guidance during nervous system development. Also, it potent immune-regulator inflammatory processes. Sema3A reportedly exerts protective effect on pruritis and skin inflammation atopic dermatitis (AD), suggesting possibility of Seme3A to be therapeutic target AD. Given that expression coordinately mediated by keratinocyte differentiation activation aryl hydrocarbon receptor (AHR), ligand-activated transcriptional factor, promotes differentiation, we hypothesized may regulated AHR human keratinocytes. To test this, analyzed normal epidermal keratinocytes (NHEKs) treated with tapinarof, AHR-modulating agent for the treatment We found tapinarof upregulated mRNA protein levels either monolayer- or 3D- cultured NHEKs. Since activates NRF2 (Nuclear factor erythroid 2-related 2), examined whether affected upregulation induced tapinarof. Knockdown using siRNA transfection abolished tapinarof-induced upregulation, indicating modulated via AHR-NRF2 axis. further clarify mechanism, cloned promoter region gene identified an antioxidant response element (ARE)-like loci (AREL) within -209 base pairs start codon was critical activity. confirmed activated bound AREL ChIP analysis. Taken together, our findings provide first evidence could have potential upregulate viathe axis, leading improvement