Abstract
Skin barrier dysfunction, including reduced filaggrin (FLG) and loricrin (LOR) expression, plays a critical role in atopic dermatitis (AD) development. Since aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, mediates keratinocyte differentiation, it is a potential target for AD treatment. Recently, clinical studies have shown that tapinarof, an AHR modulator, attenuated the development of AD. To examine the molecular mechanism involved in this, we analyzed tapinarof-treated normal human epidermal keratinocytes (NHEKs). Tapinarof upregulated FLG and LOR mRNA and protein expression in an AHR-dependent manner. Tapinarof also induced the secretion of IL-24, a cytokine that activates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), leading to the downregulation of FLG and LOR expression. Knockdown of either IL-24 or STAT3 expression by small interfering RNA (siRNA) transfection augmented the upregulation of FLG and LOR expression induced by tapinarof, suggesting that inhibition of the IL-24/STAT3 axis during AHR activation supports the improvement of skin barrier dysfunction. Furthermore, tapinarof alone could restore the downregulation of FLG and LOR expression induced by IL-4, a key cytokine of AD, and its combination with JAK inhibitors enhanced this effect. These findings provide a new strategy for treating AD using AHR modulators and JAK inhibitors.
Highlights
Atopic dermatitis (AD) is a very common, chronic inflammatory skin disease [1]
To investigate how the expression of FLG and LOR was mediated by aryl hydrocarbon receptor (AHR) activation, we examined their expression in normal human epidermal keratinocytes (NHEKs) treated with tapinarof
NHEKs were treated with dimethyl sulfoxide (DMSO), baricitinib (1 μM), or JTE-052 (1 μM) in the presence or absence of tapinarof (500 nM) for Quantitative Reverse-Transcription (qRT)-PCR and Western blotting analyses of FLG and LOR
Summary
Atopic dermatitis (AD) is a very common, chronic inflammatory skin disease [1]. Since skin barrier defects facilitate allergen priming, leading to allergic responses, improving skin barrier dysfunction is vital in treating AD [2,3]. Our previous studies reported that activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, upregulates the expression of filaggrin (FLG) and loricrin (LOR), which are essential proteins in skin barrier functions [4,5,6]. Since reduced FLG and LOR expression contributes to the development of AD [3], restoring skin barrier functions via AHR activation is beneficial for treating AD. Previous studies, including ours, have reported that AHR ligands, including coal tar, soybean tar, and 6-formylindolo[3,2-b]carbazole (FICZ), could improve skin barrier dysfunction in AD [7,8,9,10], suggesting that an AHR ligand could become a therapeutic agent for treating AD. It has been demonstrated that tapinarof activates the AHR-NRF2 axis [13], leading to the inhibition of inflammation [11], whether tapinarof modulates skin barrier dysfunction in AD has remained unclear
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