Activation of IL1A/IRAK1 axis and downstream proinflammatory signaling in healthy adult and neonatal African American skin

Abstract

Differences in prevalence of inflammatory skin diseases including atopic dermatitis and psoriasis in African American (AA) versus White Non-Hispanic (WNH) population are well recognized. However, the underlying mechanisms are largely unknown. We previously observed significant differences in healthy AA skin transcriptome with differentially expressed genes (DEG) enriched for inflammation and cornification processes. Here we analyzed proteome in skin biopsies from healthy AA and WNH volunteers using Olink(R) Explore Inflammation 384 biomarker panel. Among proteins with higher expression in AA skin were IRAK1, IL1A, IL4, IL22RA1. IL1A binding to IL1R1 receptor is known to result in recruitment of adapter molecules such as IRAK1, and activation of downstream NF-{kappa}B and MAPK signaling. We confirmed NF-{kappa}B and ERK1/2 activation in AA skin by Western blot analysis of their phosphorylation at specific activating sites. Importantly, we observed similar differences between AA and WNH neonatal foreskin and between AA and WNH 3D skin organoids. Further analysis of DEG promoters by Gene Transcription Regulation Database (GTRD) pointed to NF-{kappa}B and AP1 as key transcription factors involved in AA DEG regulation. Overall, proinflammatory signaling in healthy AA skin starting early in childhood may contribute to the increased risk of certain inflammatory skin diseases within the AA population.