Overexpression of NPY leads to a progressive, cutaneous inflammatory fibrotic response in mouse skin.

Neuropeptide Y (NPY) is a pleiotropic peptide produced in the central nervous system and peripheral organs and is upregulated in some human skin conditions like atopic dermatitis. We reported previously that a knock-in mouse with entopic NPY overexpression (NPYtet/tet) exhibits significantly elevated NPY gene and protein expression in the skin, accompanied by premature and progressive hair graying. However, the question remained whether NPY overexpression induces other skin pathologies. RNA-seq was used to show changes in the transcriptome in 35-week-old NPY overexressing mice, allowing us to highlight transcriptional changes using downstream analysis. Using a cross-sectional approach focused on timepoints before and after the onset of graying, we find that overexpression of NPY results in transcriptomic changes associated with inflammation and fibrosis. The histopathology of NPYtet/tet mice following hair graying included increased epidermal proliferation and an increase in CD3+ dendritic epidermal T cells. The dermis of NPYtet/tet mice exhibited enhanced fibrotic changes with abnormal rearrangement of collagen bundles and widespread dermal infiltration of degranulated mast cells and CD206+ M2 macrophages. NPYtet/tet mice also showed a thinning of the intradermal fat layer with focal areas of panniculitis. These results provide long-awaited evidence of NPY’s involvement in skin pathology, a background for defining the precise role of NPY in the regulation of skin homeostasis, and highlights its potential impact in inflammatory and/or fibrotic disorders.