Activation of the VEGFR-3 Pathway by VEGF-C Attenuates UVB-Induced Edema Formation and Skin Inflammation by Promoting Lymphangiogenesis
Activation of the VEGFR-3 Pathway by VEGF-C Attenuates UVB-Induced Edema Formation and Skin Inflammation by Promoting Lymphangiogenesis
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DOI：
10.1038/jid.2008.351
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发表时间：
2009-05-01
影响因子：
6.5
通讯作者：
Detmar, Michael
中科院分区：
文献类型：
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作者：
Kajiya, Kentaro;Sawane, Mika;Detmar, Michael
我们以前已经证明，UVB照射导致皮肤淋巴管功能受损，这表明淋巴功能在UVB诱导的炎症介导中起着至关重要的作用。尽管如此，淋巴参与炎症的分子机制仍不清楚。在这里，我们发现，血管内皮生长因子（VEGF）-C的表达下调UVB照射后，与淋巴管的扩大和真皮中的巨噬细胞浸润的增加。为了确定VEGF-C/VEGFR-3信号传导的激活是否可以减少UVB诱导的炎症，将小鼠暴露于单剂量的UVB照射以及皮内注射突变体VEGF-C（Cys 156 Ser），其特异性结合淋巴管内皮上的VEGFR-3。我们发现，VEGFR-3的激活减弱UVB诱导的水肿形成，与CD 11b阳性巨噬细胞的数量减少。此外，突变VEGF-C注射液抑制UVB诱导的淋巴管扩张，也诱导淋巴管内皮细胞增殖。相比之下，用突变VEGF-C治疗对血管大小或数量没有影响。这些结果表明，UVB诱导的淋巴损伤介导的VEGF-C的表达下调和VEGFC/VEGFR-3途径的激活可能是一个可行的目标，通过促进淋巴管生成的UVB诱导的炎症预防。
We have previously demonstrated that UVB irradiation resulted in impaired function of cutaneous lymphatic vessels, suggesting a crucial role of lymphatic function in the mediation of UVB-induced inflammation. Nonetheless, the molecular mechanisms of lymphatic involvement in inflammation have remained unclear. Here, we show that vascular endothelial growth factor (VEGF)-C expression is downregulated after UVB irradiation, associated with enlargement of lymphatic vessels and with an increase of macrophage infiltration in the dermis. To determine whether activation of VEGF-C/VEGFR-3 signaling might reduce UVB-induced inflammation, mice were exposed to a single dose of UVB irradiation together with intradermal injection of mutant VEGF-C (Cys156Ser), which specifically binds to VEGFR-3 on lymphatic endothelium. We found that the activation of VEGFR-3 attenuated UVB-induced edema formation, associated with a decreased number of CD11b-positive macrophages. Moreover, mutant VEGF-C injection inhibited UVB-induced enlargement of lymphatic vessels and also induced the proliferation of lymphatic endothelial cells. In contrast, treatment with mutant VEGF-C had no effect on blood vessel size or number. These results demonstrate that UVB-induced lymphatic impairment is mediated by downregulation of VEGF-C expression and that the activation of the VEGFC/VEGFR-3 pathway might represent a feasible target for the prevention of UVB-induced inflammation by promoting lymphangiogenesis.