Epidermal ROR maintains barrier integrity and prevents allergic inflammation by regulating late differentiation and lipid metabolism

The skin epidermis provides a vital barrier for preventing transepidermal water loss (TEWL) and environmental stimuli. However, the molecular mechanisms ensuring barrier integrity remain not fully understood. ROR is a nuclear receptor highly expressed in the epidermis of normal skin. However, its epidermal expression is significantly reduced in the lesions of multiple inflammatory skin diseases. In this study, using mice with epidermis-specific Rora gene deletion (RoraEKO), we have demonstrated the central roles of ROR in stabilizing skin barrier function. Albeit the lack of spontaneous skin lesion or dermatitis, RoraEKO mice exhibited elevated TEWL rate and skin features indicating barrier dysfunction. The histological and lipidomic analysis uncovered low levels of cornified envelope proteins and aberrant ceramide composition in the RoraEKO epidermis, implying disturbed late epidermal differentiation. In parallel, RNA-seq analysis revealed altered transcription levels of gene clusters related to keratinization and lipid metabolism in ROR deficient epidermis. Importantly, epidermal Rora ablation greatly amplified percutaneous allergic inflammatory responses to oxazolone in a mouse allergic contact dermatitis (ACD) model. Our results substantiated the essence of epidermal ROR in maintaining late keratinocyte differentiation and normal barrier function while suppressing cutaneous inflammation. To investigate the in vivo role of epidermal ROR in regulating keratinocyte differentiation and skin inflammation, we established a mouse strain with epidermis-specific Rora gene.