Myeloid-Specific Blockade of Notch Signaling Attenuates Choroidal Neovascularization through Compromised Macrophage Infiltration and Polarization in Mice
Myeloid-Specific Blockade of Notch Signaling Attenuates Choroidal Neovascularization through Compromised Macrophage Infiltration and Polarization in Mice
复制标题
骨髓特异性阻断 Notch 信号传导通过受损的巨噬细胞浸润和极化来减弱脉络膜新生血管形成
DOI：
10.1038/srep28617
复制
发表时间：
2016-06-24
影响因子：
4.6
通讯作者：
Wang, Yu-Sheng
中科院分区：
文献类型：
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作者：
Dou, Guo-Rui;Li, Na;Wang, Yu-Sheng
巨噬细胞已被认为是脉络膜新生血管（CNV）中的重要炎症成分。然而，目前尚不清楚这些细胞如何被激活和极化、它们如何影响血管生成以及 CNV 过程中的潜在机制是什么。 Notch 信号传导与巨噬细胞激活有关。此前我们已经表明，在成年小鼠中，Notch 信号传导的关键转录因子 RBP-J 的诱导性破坏会导致 CNV 增强，但尚不清楚巨噬细胞特异性 Notch 信号传导在 CNV 发展中的作用。在目前的研究中，通过使用骨髓特异性RBP-J敲除小鼠模型与激光诱导CNV模型相结合，我们发现巨噬细胞中Notch信号传导的破坏表现出CNV生长减弱，巨噬细胞浸润和活化减少，并减轻激光诱导后的血管生成反应。在骨髓特异性 RBP-J 敲除小鼠中，CNV 的抑制伴随着浸润炎症巨噬细胞中 VEGF 和 TNF-α 表达的降低。正如体外研究所示，这些变化可能会导致 EC 腔形成的直接抑制。因此，CNV中Notch信号传导的临床干预需要精确定位髓系谱系，以避免整体抑制的反作用。
Macrophages have been recognized as an important inflammatory component in choroidal neovascularization (CNV). However, it is unclear how these cells are activated and polarized, how they affect angiogenesis and what the underlining mechanisms are during CNV. Notch signaling has been implicated in macrophage activation. Previously we have shown that inducible disruption of RBP-J, the critical transcription factor of Notch signaling, in adult mice results in enhanced CNV, but it is unclear what is the role of macrophage-specific Notch signaling in the development of CNV. In the current study, by using the myeloid specific RBP-J knockout mouse model combined with the laser-induced CNV model, we show that disruption of Notch signaling in macrophages displayed attenuated CNV growth, reduced macrophage infiltration and activation, and alleviated angiogenic response after laser induction. The inhibition of CNV occurred with reduced expression of VEGF and TNF-alpha in infiltrating inflammatory macrophages in myeloid specific RBP-J knockout mice. These changes might result in direct inhibition of EC lumen formation, as shown in an in vitro study. Therefore, clinical intervention of Notch signaling in CNV needs to pinpoint myeloid lineage to avoid the counteractive effects of global inhibition.