Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation.
Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation.
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DOI：
10.1084/jem.20100559
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发表时间：
2010-09-27
期刊：
影响因子：
--
通讯作者：
Detmar M
中科院分区：
文献类型：
--
作者：
Huggenberger R;Ullmann S;Proulx ST;Pytowski B;Alitalo K;Detmar M
淋巴管生成在炎症中的作用仍不清楚。为了研究淋巴管与血管系统在慢性皮肤炎症中的作用，我们在建立的慢性皮肤炎症的角蛋白14（K14）-VEGF-A转基因（Tg）小鼠模型中通过功能阻断抗体抑制血管内皮生长因子（VEGF）受体（VEGFR）信号传导。尽管抗VEGFR-2抗体治疗可抑制皮肤炎症、表皮增生、炎症性浸润和血管生成，但令人惊讶的是，全身抑制VEGFR-3，尽管抑制了淋巴管生成，但仍增加了炎症性水肿形成和炎症细胞积聚。重要的是，淋巴管生成因子VEGF-C向K14-VEGF-A小鼠皮肤的长期Tg递送完全抑制了慢性皮肤炎症、表皮增生和异常分化的发展以及CD 8 T细胞的积累。在Tg递送小鼠VEGF-D后发现类似的结果，其仅活化VEGFR-3而不活化VEGFR-2。此外，皮内注射仅激活VEGFR-3的重组VEGF-C156 S显著减少炎症。尽管淋巴引流在慢性皮肤炎症中被抑制，但Tg VEGF-C递送增强了淋巴引流。总之，这些结果揭示了淋巴管在控制慢性炎症中的意想不到的积极作用。因此，除了抗血管生成治疗外，通过VEGFR-3刺激功能性淋巴管生成可能作为治疗皮肤和其他器官慢性炎症性疾病的新策略。
The role of lymphangiogenesis in inflammation has remained unclear. To investigate the role of lymphatic versus blood vasculature in chronic skin inflammation, we inhibited vascular endothelial growth factor (VEGF) receptor (VEGFR) signaling by function-blocking antibodies in the established keratin 14 (K14)–VEGF-A transgenic (Tg) mouse model of chronic cutaneous inflammation. Although treatment with an anti–VEGFR-2 antibody inhibited skin inflammation, epidermal hyperplasia, inflammatory infiltration, and angiogenesis, systemic inhibition of VEGFR-3, surprisingly, increased inflammatory edema formation and inflammatory cell accumulation despite inhibition of lymphangiogenesis. Importantly, chronic Tg delivery of the lymphangiogenic factor VEGF-C to the skin of K14-VEGF-A mice completely inhibited development of chronic skin inflammation, epidermal hyperplasia and abnormal differentiation, and accumulation of CD8 T cells. Similar results were found after Tg delivery of mouse VEGF-D that only activates VEGFR-3 but not VEGFR-2. Moreover, intracutaneous injection of recombinant VEGF-C156S, which only activates VEGFR-3, significantly reduced inflammation. Although lymphatic drainage was inhibited in chronic skin inflammation, it was enhanced by Tg VEGF-C delivery. Together, these results reveal an unanticipated active role of lymphatic vessels in controlling chronic inflammation. Stimulation of functional lymphangiogenesis via VEGFR-3, in addition to antiangiogenic therapy, might therefore serve as a novel strategy to treat chronic inflammatory disorders of the skin and possibly also other organs.
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影响因子：
11.2
作者：
Hoshida, Tohru;Isaka, Naohide;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.
影响因子：
4.4
作者：
Cursiefen, C;Cao, JT;Streilein, JW
通讯作者：
Streilein, JW
影响因子：
10.3
作者：
Bhushan, M;McLaughlin, B;Griffiths, CEM
通讯作者：
Griffiths, CEM
影响因子：
20.3
作者：
Halin, Cornelia;Tobler, Nadja E.;Detmar, Michael
通讯作者：
Detmar, Michael
DOI：
10.1084/jem.180.3.1141
发表时间：
1994-09-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Detmar M;Brown LF;Claffey KP;Yeo KT;Kocher O;Jackman RW;Berse B;Dvorak HF
通讯作者：
Dvorak HF