TRPA1 ion channel activation context‐dependently regulates gene expression in normal and psoriatic human skin

Psoriasis is a chronic, relapsing, immune-mediated inflammatory skin disease. The transient receptor potential ankyrin 1 (TRPA1) ion channel plays a protective role in the formation of psoriasiform skin reactions. Here, we investigated the pharmacological activation and blockade of TRPA1 in human skin (patho)physiology. Six-millimetre full-thickness biopsies were obtained from psoriatic lesional and non-lesional skin of four patients with psoriasis, and from normal skin of four healthy volunteers. Each biopsy was quartered: One segment was untreated, and the other three were cultured with vehicle (DMSO), TRPA1 agonist mustard oil (MO), or TRPA1 antagonist (HC030031), respectively. Global gene expression was measured by RNA sequencing, followed by differential expression and functional enrichment analyses, to identify TRPA1-modulated genes. Pre-evaluation of data with ordination assessment showed clear cluster formation according to treatments and condition of the skin. In healthy skin, TRPA1 activation down-regulated genes associated with interferon signalling, antimicrobial responses, and inflammation/oxidative stress. In lesional psoriatic skin, the genes of interleukin-4 (IL-4), IL-10 and IL-13 cytokine signalling-related proteins, circadian gene expression, and senescence-associated secretory phenotype (SASP) genes were down-regulated by MO treatment. Antagonist treatment did not cause significant gene expression changes, supporting the previous finding that basal TRPA1 activity is low in the skin. DMSO treatment in all three conditions increased expression of several inflammatory genes, which was normalised during data analysis. Exploration of the interactions between TRPA1 and identified signalling pathways may open new opportunities to target psoriasis, alleviate disease symptoms and optimise therapies.