Involucrin Modulates Vitamin D Receptor in the

Terminally differentiated keratinocytes are critical for epidermal function and are surrounded by involucrin (IVL). Increased IVL expression is associated with a near-selective sweep in European populations compared with those in Africa. This positive selection for increased IVL in the epidermis identifies human adaptation outside of Africa. The functional significance is unclear. We hypothesize that IVL modulates the environ-mentally sensitive vitamin D receptor (VDR) in the epidermis. We investigated VDR activity in Ivl / and wild -type mice using vitamin D agonist (MC903) treatment and comprehensively determined the inflammatory response using single-cell RNA sequencing 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 thorn T cells, basophils, macrophages, monocytes, and type II basal keratinocytes and an increase in suprabasal keratinocytes. Coinciding with the dampened MC903-mediated inflammation, the skin microbiota of Ivl / mice was more stable than that of the wild-type mice, which exhibited an MC903-responsive increase in Bacteroidetes and a decrease in Firmicutes. Together, our studies in Ivl / mice identify a functional role for IVL to positively impact VDR activity and an IVL/VDR for in the human

Automated summary

Increased IVL expression shows positive selection and plays a role in regulating VDR activity, affecting skin inflammation and microbiota stability in the epidermis.