178 The LRRC8 ion channel as novel drug target for psoriasis

Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation and aberrant keratinocyte differentiation. Since newer findings suggested that cell volume changes drive cellular differentiation, it of medical interest to better understand regulation in healthy pathological conditions. Hence, the aim our study was identify ion channels involved epidermal evaluate their suitability as novel drug targets psoriasis. We first performed RNA Seq analysis isolated stem cells, transient amplifying postmitotic cells identified genes coding for heterohexameric LRRC8 channel among differentially expressed (DEGs). Immunohistological stainings revealed expression major subunit LRRC8A almost exclusively basal layer. Strikingly, staining drastically reduced lesional psoriasis patients. generated knockout (KO) keratinocytes CRISPR-Cas9 observed KO completely lack osmotically-induced Cl- currents resulting delayed regulatory decrease. Moreover, we found 2D 3D vitro differentiation cells. Comparison transcriptome WT showed modified cycle marker genes. Analysis publically available data appear frequently DEGs psoriatic LRRC8A-KO mice display hyperkeratosis. Finally, compound screening diverse chemical structures activators LRRC8, which tioxolon, known active ingredient topical formulations treatment psoriasis, highlights potential developing small-molecule compounds specifically targeting treatment. Altogether propose target may serve lead development.