O06 Comparative spatial transcriptomics of inflammatory skin conditions identifies a potential therapeutic target for keratosis pilaris

Abstract Introduction and aims Keratosis pilaris (KP) is a common dermatological condition characterized by small, rough bumps on the skin’s surface, often affecting the outer arms and thighs; it is present in over 50% of teenagers and up to 40% of adults. KP results from abnormal follicular keratinization whereby shedding corneocytes fill hair follicles rather than exfoliating, creating a ‘plug’ with associated perifollicular inflammation. Treatments remove an excess of the outermost dead skin layers, but do not target the cause of KP, only the symptoms. A greater understanding of the cellular and molecular mechanisms contributing to KP is needed. Methods Spatial transcriptomics is a powerful technique to investigate gene expression patterns in their spatial context within complex tissues. We applied 10X-Visium technology to samples of human skin with (n = 1) and without (n = 10) KP, and compared these results to publicly available data from atopic eczema (n = 7) and psoriasis (n = 11), with significance calculated using the Wilcoxon rank sum test. Selected findings were functionally validated using human primary keratinocytes in monolayer and skin organotypic models. Results KP skin shows increased gene expression for keratinocyte differentiation markers including FLG, the gene encoding filaggrin. One candidate gene (CG1; gene name redacted to protect intellectual property) showed a marked upregulation (log2 fold change = 1.44, P < 0.001) with specificity for KP over eczema or psoriasis. CG1 plays a role in cell–cell and cell–matrix interactions but little else is known about its role in keratinocytes. Addition of recombinant CG1 to monolayers and organotypics increased gene expression pathways mediating acute inflammation and regulation of wound healing, and increased stratum corneum thickness. Conversely, knockdown of CG1 decreased expression of multiple keratinocyte differentiation markers. Conclusions These findings begin to shed light on the complex pathogenesis of KP and offer promising avenues for the development of targeted therapies aimed at ameliorating this common skin condition.