Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. (June 2019) - Hasan, Md Zobaer
Abstract: The incidence of sensitive skin with stinging and itch following chemical exposure in products such as cosmetics is increasing, but molecular mechanisms underlying this pathophysiology remain understudied. Here we performed transcriptional analysis of reconstructed human epidermis (RHE) 1, 6, and 24 h following topical lactic acid (LA) application, a known inducer of the sensitive skin reaction. Since little is known about the specific role of keratinocyte transcriptional changes in mediating stinging and itch, we performed pathway analysis using several publically available databases and then focused on significantly changed transcripts involved in stress responses and itch signaling using the Comparative Toxicogenomics Database. LA treatment induced damage-associated genes HSPA1A, DDIT3, IL1A, and HMGB2. Neurotrophic factors including BDNF, ARTN, PGE2, and chemokines were also upregulated. Stimulation of the RHE with 5% LA did not reduce cell viability, but reduced the trans-epidermal electric resistance, suggesting barrier dysfunction. Accordingly, skin barrier formation genes such as filaggrins (FLG, FLG2) and corneodesmosin (CDSN) were downregulated. To our knowledge, this is the first study focusing on transcriptional changes underlying the stinging response of keratinocytes upon LA stimulation. While follow-up research is needed, this study provides new insight into the mechanisms underlying the sensitive skin reaction. Highlights: Microarray analysis following lactic acid stimulation of reconstituted human epidermis reveals a gene signature for itch. Transcripts induced by lactic acid stimulation cluster in pathways involved in stress responses and water loss via skin. Skin barrier formation and function transcripts were downregulated following lactic acid stimulation. Molecular mechanisms underlying sensitive skin syndrome can be studied using reconstituted human epidermis. Understanding keratinocyte responses to lactic acid may increase clinical utility in sensitive skin syndrome.