Involucrin Modulates Vitamin D Receptor Activity in the Epidermis

Area of Science:

• Human adaptation
• Epidermal biology
• Immunology

Background:

• Terminally differentiated keratinocytes are crucial for skin barrier function.
• Involucrin (IVL) expression shows a selective sweep in European populations, suggesting adaptation.
• The functional role of increased IVL in human adaptation remains unclear.

Purpose of the Study:

• To investigate the functional significance of Involucrin (IVL).
• To test the hypothesis that IVL modulates the vitamin D receptor (VDR) in the epidermis.
• To explore the impact of IVL on skin inflammation and microbiome.

Main Methods:

• Utilized Ivl knockout (Ivl-/-) and wild-type mice.
• Administered a vitamin D agonist (MC903) to assess VDR activity and inflammatory responses.
• Employed single-cell RNA sequencing and 16S bacterial phylotyping to analyze skin inflammation and microbiome changes.

Main Results:

• Reduced VDR activity and target gene expression in Ivl-/- mouse skin.
• Dampened MC903-induced skin inflammation in Ivl-/- mice, with altered immune cell populations (decreased CD4+ T cells, basophils, macrophages, monocytes, type II basal keratinocytes; increased suprabasal keratinocytes).
• Increased skin microbiota stability in Ivl-/- mice, contrasting with MC903-induced shifts in wild-type mice (increase in Bacteroidetes, decrease in Firmicutes).

Conclusions:

• Identified a functional role for Involucrin (IVL) in positively regulating Vitamin D Receptor (VDR) activity.
• Suggests an emerging Involucrin/Vitamin D Receptor (IVL/VDR) paradigm for human adaptation.
• Highlights the interplay between epidermal proteins, VDR signaling, and skin microbiome in adaptation.