Psoriasis is a common chronic skin disorder characterized by keratinocyte hyperproliferation with altered differentiation accompanied by inflammation and increased angiogenesis. It remains unclear whether the first events that initiate psoriasis development occur in keratinocytes or inflammatory cells. Here, using different psoriasis mouse models, we showed that conditional deletion of Flt1 or Nrp1 in epidermal cells inhibited psoriasis mediated by Vegfa overexpression or c-Jun/JunB deletion. Administration of anti-Nrp1 antibody reverted the psoriasis phenotype. Using transcriptional and chromatin profiling of epidermal cells following Vegfa overexpression together with Flt1 or Nrp1 deletion, we identified the gene regulatory network regulated by Vegfa/Nrp1/Flt1 during psoriasis development and uncovered a key role of Fosl1 in regulating the chromatin remodeling mediated by Vegfa overexpression in keratinocytes. In conclusion, our study identifies an epidermal autonomous function of Vegfa/Nrp1/Flt1 that mediates psoriatic-like disease and demonstrates the clinical relevance of blocking Vegfa/Nrp1/Flt1 axis in psoriasis.

中文翻译：

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表皮自主VEGFA / Flt1 / Nrp1的功能介导牛皮癣样疾病。

牛皮癣是一种常见的慢性皮肤病，其特征在于角质形成细胞过度增殖，分化改变，伴有炎症和血管生成增加。尚不清楚启动牛皮癣发展的最初事件是否发生在角质形成细胞或炎性细胞中。在这里，我们使用不同的银屑病小鼠模型，我们发现表皮细胞中Flt1或Nrp1的条件缺失抑制了由Vegfa过表达或c-Jun / JunB缺失介导的牛皮癣。抗Nrp1抗体的使用恢复了牛皮癣的表型。在Vegfa过表达以及Flt1或Nrp1缺失后，使用表皮细胞的转录和染色质分析，我们确定了在牛皮癣发展过程中由Vegfa / Nrp1 / Flt1调控的基因调控网络，并揭示了Fosl1在调节由Vegfa过度表达于角质形成细胞介导的染色质重塑中的关键作用。总之，我们的研究确定了介导牛皮癣样疾病的Vegfa / Nrp1 / Flt1的表皮自主功能，并证明了在牛皮癣中阻断Vegfa / Nrp1 / Flt1轴的临床意义。