Ergosterol, a Novel RORγt Inverse Agonist, Enhances Skin Barrier Function and Reduces Skin Inflammation in IMQ‐Induced Mice With Psoriasis

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ABSTRACT Retinoic acid receptor‐related orphan receptor gamma‐t (RORγt) is one of the nuclear receptor transcription factors that plays a key role in the differentiation of pro‐inflammatory IL‐17 + T helper cells. Recently, RORγt has attracted increasing attention as a potential drug target for the treatment of several human inflammatory diseases, including psoriasis and Crohn's disease. In this study, we revealed that ergosterol (ERG) was a novel RORγt inverse agonist, which decreased RORγt transcriptional activity, to regulate collagen fiber deposition and to inhibit pro‐inflammatory cytokines, including TNF‐α, IL‐1β, IL‐6, IL‐17, IL‐22, and IL‐23 in the skin lesions of IMQ‐induced mice with psoriasis. Furthermore, ERG could repair the epidermal barrier function by upregulating tight junction proteins, such as claudin, occludin, and ZO‐1, thereby alleviating psoriasis symptoms. These findings suggested that ERG might be used as a promising novel RORγt inverse agonist in the management of psoriasis.

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