Terminally differentiated keratinocytes are critical for epidermal function and surrounded by involucrin (IVL). Increased IVL expression is associated with a near selective sweep in European populations compared to African. This positive selection for increased IVL in the epidermis identifies human adaptation out-of-Africa. The functional significance is unclear. We hypothesize Ivl to modulate the environmentally sensitive Vitamin D receptor (Vdr) in the epidermis. We investigated Vdr activity in Ivl -/- and wild-type (WT) mice using vitamin D agonist (MC903) treatment and comprehensively determined the inflammatory response using single-cell RNA sequencing (scRNA-seq) and associated skin microbiome changes using 16S bacterial phylotyping. Vdr activity and target gene expression were reduced in Ivl -/- mouse skin, with decreased MC903-mediated skin inflammation and significant reductions in CD4+ T cells, basophils, macrophages, monocytes, and type II basal keratinocytes and increase in suprabasal keratinocytes. Coinciding with the dampened MC903-mediated inflammation, skin microbiota of Ivl -/- mice was more stable compared to WT mice, which exhibited a MC903-responsive increase in Bacteroidetes and decrease in Firmicutes. Together, our studies in Ivl -/- mice identify a functional role for Involucrin to positively impact Vdr activity and suggest an emerging IVL/VDR paradigm for adaptation in the human epidermis
