Chronic overexpression of neuropeptide Y in the skin is sufficient to induce inflammation and epidermal and dermal pathology

Abstract 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 the 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 regulatory T cells 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 and highlights novel cell types involved in the NPY-mediated response in the skin. Together, these results provide long-awaited evidence of NPY’s involvement in skin pathology, providing a background for defining the precise role of NPY in the regulation of cutaneous homeostasis and disease.