Exploring retinoic acid-induced skin irritation: Pathological and mechanistic insights from an ex vivo porcine skin model

All-trans retinoic acid (RA) is widely used to treat various skin conditions but it often produce adverse effects like erythema, and dryness. However, histological characteristics and molecular mechanisms of RA-induced skin irritation were poorly understood. We investigated RA-induced skin irritation using ex vivo porcine skin model to fill this knowledge gap. Ex vivo porcine skin was treated with RA and examined for histological and molecular changes. Single or repeated exposure of RA caused mild irritant responses without significantly affecting tissue viability of ex vivo porcine skin. However, microscopical inspection revealed the cell swelling and slight nuclear shrinkage of keratinocytes. RA induced epidermal thickening through basal keratinocyte proliferation but decreased the thickness of cornified layer and elevated trans-epidermal water loss (TEWL), demonstrating the barrier disruptive effects. Pro-inflammatory cytokines IL-1β, IL-8, and MCP-1 were upregulated by RA in ex vivo porcine skin. RA increased p-p38, p-ERK, p-JNK, p-IκB and importantly caspase-1 in HaCaT cells supporting the activation of inflammasome pathway. Collectively, RA-induced skin irritation was driven by epidermal proliferation and inflammation. The ex vivo porcine skin model can recapitulate the RA-induced skin irritation, providing a reliable and cost-effective alternative method for research on dermatitis.