34982 Transcriptome analysis reveals intrinsic proinflammatory signaling in healthy African American skin

Abstract

Background: The disparities in prevalence and clinical features for many inflammatory skin diseases including atopic dermatitis and psoriasis are well recognized; however, the underlying mechanisms are largely unknown. Methods: Using bulk RNA-seq analysis, we compared the baseline gene expression in upper arm full thickness skin biopsies from 17 healthy individuals self-reporting as African American (AA) or White non-Hispanic (WNH) and in 3D human skin equivalents (HSE) made from AA and WNH primary skin keratinocytes. Results: Extensively validated RNA-Seq analysis identified 570 differentially expressed genes (DEG) in AA skin including immunoglobulins and their receptors such as FCER1G; proinflammatory genes such as TNFα, IL-32; EDC (epidermal differentiation cluster) and keratin genes. DEGs were functionally enriched for inflammatory responses, keratinization, cornified envelope formation. RNA-seq analysis of gene expression in AA versus WNH HSEs revealed 360 DEGs (some shared with skin) which were enriched by similar to skin functions. In addition, AA HSE appeared more responsive to TNFα proinflammatory effects. Finally, AA-specific DEGs in skin and HSE significantly overlapped with molecular signatures of lesional skin in AD and psoriasis patients. Interestingly, AA skin DEGs overlapping with AD molecular signature in skin were enriched by IL13 and IL4 signaling central for AD. Conclusions: Overall, these findings suggest the existence of intrinsic proinflammatory 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 and treatment.