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. B6;129S4-Npytm2Rpa/J mice (NPY tet/tet) and their wildtype siblings (NPY +/+) were aged to 35 weeks of age before being euthanized, with whole skin being harvested for RNA extraction and analysis

神经肽Y（Neuropeptide Y, NPY）是一种多效肽，可在中枢神经系统与外周器官中合成，并在特应性皮炎等部分人类皮肤疾病中表达上调。本课题组此前曾报道，携带原位NPY过表达的敲入小鼠（NPYtet/tet）的皮肤组织中，NPY基因与蛋白表达水平显著升高，同时伴随早发性且进行性的毛发变白。但此前仍存在一个未明确的疑问：NPY过表达是否会诱发其他皮肤病理变化？本研究采用RNA测序（RNA-seq）技术，对35周龄的NPY过表达小鼠的转录组变化进行分析，并通过下游分析明确相关转录水平的改变。本研究采用横断面研究设计，聚焦于毛发变白发生前后的时间节点，结果发现NPY过表达可引发与炎症及纤维化相关的转录组改变。毛发变白症状出现后，NPYtet/tet小鼠的组织病理学表现为表皮增殖增强、CD3+树突状表皮T细胞数量增多。NPYtet/tet小鼠的真皮层可见纤维化改变加重，胶原束排列异常，同时存在脱颗粒肥大细胞与CD206+ M2巨噬细胞的广泛真皮浸润。此外，NPYtet/tet小鼠还出现真皮内脂肪层变薄，并伴随局灶性脂膜炎。本研究结果为NPY参与皮肤病理过程提供了期待已久的证据，为明确NPY在皮肤稳态调控中的精准作用奠定了研究基础，并凸显了其在炎症性和/或纤维化性皮肤疾病中的潜在影响。实验中，研究人员将B6;129S4-Npytm2Rpa/J小鼠（即NPYtet/tet）及其野生型同窝小鼠（NPY +/+）饲养至35周龄后实施安乐死，采集全皮肤组织用于RNA提取与后续分析。