569 Transcriptome analysis reveals intrinsic pro-inflammatory signaling in healthy African American skin

Abstract

Differences in morphology and physiology of darkly pigmented compared to lightly pigmented skin are well recognized. There are also disparities in prevalence and clinical features for many inflammatory skin diseases including atopic dermatitis (AD) and psoriasis; however, the underlying mechanisms are largely unknown. We compared the baseline gene expression in full thickness skin biopsies from healthy individuals with Fitzpatrick skin type V-VI or I-II, and self-reported as either African American (AA) or White Non-Hispanic (WNH). Extensively validated RNA-Seq analysis identified 670 differentially expressed genes (DEG) in AA skin including immunoglobulins (Igs) and their receptors such as FCER1G; pro-inflammatory genes such as TNFα, IL-32; EDC (epidermal differentiation cluster) and keratin genes. DEGs were functionally enriched for inflammatory responses, keratinization/cornified envelope formation. Analysis of putative transcription factors involved in AA DEG regulation revealed pro-inflammatory NF-kB, regulator of Igs OCT1, and KLF4 important for skin barrier development. RNA-Seq analysis of 3D human skin equivalents (3D HSE) made from AA and WNH epidermal keratinocytes revealed more than 300 DEGs enriched by similar functions as in skin. AA 3D HSE were more responsive to TNFα pro-inflammatory effects. Most genes induced by 24h TNFα treatment in AA 3D HSE were functionally enriched for inflammation, whereas a majority of DEGs were linked to GSEA categories related to ECM and collagen fibers organization/degradation and MMP activation in CA samples. Finally, AA-specific DEGs in skin and 3D HSE significantly overlapped with molecular signatures of pre-lesional and even lesional skin in AD and psoriasis patients. Overall, these findings suggest the existence of intrinsic pro-inflammatory circuits in AA keratinocytes/skin that may account for disease disparities and will help to build a foundation for the development of targeted skin disease prevention approaches.