mRNA sequencing of skins isolated from B6;129S4-Npytm2Rpa/J homozygous mice and wildtype litter mates reveals transcriptomic changes indicative of skin inflammation associated with Npy overexpression.

Neuropeptide Y (NPY) is a pleiotropic peptide produced in the central nervous system and peripheral organs. Despite conjectures that NPY may have a role in skin physiology and pathology, the effects of NPY in this organ remain poorly understood. We reported that a knock-in mouse with entopic NPY overexpression exhibits significantly elevated NPY in the skin, accompanied by premature and progressive hair graying secondary to depletion of melanocyte stem cells within hair follicles. However, the question remains as to whether NPY overexpression in the skin can induce non-melanocyte pathology. In this study, we employed this mouse to investigate consequences of skin-specific overexpression of NPY. Our findings show that chronic NPY overexpression in the skin induces dermal fibrosis and epidermal hyperkeratosis. Additionally, NPY overexpression induces significant accumulation of macrophages and T-regs in the dermis. RNA sequencing of whole skin from NPY-overexpressing mice further reveals NPY-mediated transcriptional changes consistent with inflammatory processes and inflammation-associated skin changes. Together, these results provide long-awaited evidence of NPY’s involvement in skin pathology, providing a background for future precise definition of its role in the regulation of cutaneous homeostasis. Examination of mRNA isolated from whole skin of 22-week-old homozygous B6;129S4-Npytm2Rpa/J mice (NPY tet/tet) and their wildtype siblings (NPY +/+).