A new ex vivo skin model for mechanistic understanding of putative anti-inflammatory topical therapeutics

[Display omitted] •Human ex vivo skin culture can be stimulated with cytokine cocktails to induce specific T cell mediated inflammatory states.•The induced inflammatory state in HESC incorporates multiple immune cell pathways as well as chemokine and cell barrier function gene signaling.•Gene expression profiles elicited in the HESC reflect an enhanced inflammatory state compared to those published from lesional biopsies.•Following drug treatment; target engagement and decreased inflammatory gene production are consistent with clinical biopsy data. Several in vitro models have been designed as test systems for inflammatory skin conditions, commonly using cell-culture or reconstructed human epidermis approaches. However, these systems poorly recapitulate the physiology and, importantly, the metabolism and biochemical activity of skin in vivo, whereas ex vivo skin culture models can retain these features of the tissue. Our objective was to develop a human ex vivo skin culture model to explore the pathophysiology of inflammatory dermatoses and for preclinical testing of potential therapeutic treatments. Following exogenous stimulation, tissue integrity and ability to induce inflammatory gene expression was retained, and stimulant concentrations and duration was optimised to mimic published data from inflammatory clinical biopsies of dermatitis and psoriasis patients. The validity and utility of the model was demonstrated when challenged with 5 drugs including a corticosteroid and vitamin D3 analogue, where inflammatory biomarkers were regulated in a manner consistent with the drugs’ reported in vivo mechanisms of action. This model retains important inflammatory gene signals observed in human inflammatory dermatoses for preclinical evaluation of novel therapeutics.