Pigmentation exacerbates tissue destruction and alters transcriptomic profiles in a murine model of acute skin inflammation

Bulk skin RNA sequencing revealed extensive pigmentation-dependent transcriptional remodeling, with pigmentation status emerging as the dominant source of variance. Gene set enrichment analysis demonstrated a coordinated downregulation of pathways associated with the establishment of the skin barrier (GO:0061436) in highly pigmented mice following the inflammatory challenge. At the gene level, pigmented skin demonstrated marked downregulation of epidermal structural proteins, including filaggrin, loricrin, claudin-1, and Spink5, alongside suppression of lipid-metabolic enzymes critical for stratum corneum organization, such as Elovl3 and Fads2b.

Key transcriptional regulators of keratinocyte differentiation and barrier maintenance, including Ovol1, Nrf2, ΔNp63, Grhl3, Klf4, Sp1, and the aryl hydrocarbon receptor (Ahr), were also coordinately downregulated. In parallel, stress-associated signaling pathways were upregulated. Together these findings identify pigmentation-linked suppression of epidermal differentiation and lipid programs as a potential molecular basis for increased barrier fragility under inflammatory stress, with implications for atopic dermatitis in highly pigmented skin.