Epidermal autonomous VEGFA/Flt1/Nrp1 functions mediate psoriasis-like disease
Epidermal autonomous VEGFA/Flt1/Nrp1 functions mediate psoriasis-like disease
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DOI：
10.1126/sciadv.aax5849
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发表时间：
2020-01-01
期刊：
影响因子：
13.6
通讯作者：
Blanpain, Cedric
中科院分区：
文献类型：
--
作者：
Benhadou, Farida;Glitzner, Elisabeth;Blanpain, Cedric
银屑病是一种常见的慢性皮肤病，其特征是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。目前尚不清楚是否启动银屑病发展的第一个事件发生在角质形成细胞或炎症细胞。在这里，使用不同的银屑病小鼠模型，我们发现表皮细胞中Flt1或Nrp1的条件性缺失抑制了Vegfa过表达或c-Jun/JunB缺失介导的银屑病。施用抗Nrp1抗体可逆转银屑病表型。使用转录和染色质分析表皮细胞后Vegfa过度表达与Flt1或Nrp1缺失，我们确定了基因调控网络的Vegfa/Nrp1/Flt1调节银屑病的发展，并揭示了一个关键作用Fosl1在调节染色质重塑介导的Vegfa过度表达角质形成细胞。总之，我们的研究确定了介导银屑病样疾病的Vegfa/Nrp1/Flt1的表皮自主功能，并证明了阻断Vegfa/Nrp1/Flt1轴在银屑病中的临床意义。
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.