TLR2/4 deficiency prevents oxygen-induced vascular degeneration and promotes revascularization by downregulating IL-17 in the retina.
TLR2/4 deficiency prevents oxygen-induced vascular degeneration and promotes revascularization by downregulating IL-17 in the retina.
复制标题
TLR2/4 缺陷可防止氧诱导的血管变性，并通过下调视网膜中的 IL-17 促进血运重建
DOI：
10.1038/srep27739
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发表时间：
2016-06-14
影响因子：
4.6
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
He C;Lai P;Wang J;Zhou T;Huang Z;Zhou L;Liu X
血管变性是许多人类退行性疾病的关键病理过程，需要有效的血运重建方法。然而，人们对血管变性和血运重建过程中使用的细胞和分子机制知之甚少。在这里，我们发现在氧诱导的视网膜病变（OIR）模型中，Toll 样受体 2 和 4 (TLR2/4) 双缺陷抑制高氧诱导的视网膜血管退化。值得注意的是，与野生型小鼠相比，TLR2/4−/− 小鼠在血管退化减少后经历了更多的血运重建，同时神经胶质细胞的激活也较少。从机制上讲，TLR2/4 激活可以将 Th17 细胞和调节性 T 细胞之间的平衡转向 Th17 细胞（IL-17A 的关键来源）。在 TLR2/4−/− 小鼠的 OIR 视网膜中观察到表达 IL-17A 的促炎细胞迁移和浸润较少，但调节性 T 细胞升高。巧合的是，TLR2/4 缺陷抑制了 IL-17A 的产生并增加了抗炎基因的表达。此外，IL-17A 促进神经胶质细胞的活化。使用中和抗体阻断 IL-17A 可减轻 C57/B6-OIR 小鼠的视网膜细胞凋亡和神经胶质细胞活化，这证明了 IL-17A 通路在血运重建过程中神经胶质细胞功能中的重要作用。因此，TLR2/4介导的IL-17A炎症信号传导参与血管变性和血运重建，表明TLR2/4-IL-17A途径的调节可能是退行性疾病的一种新的治疗策略。
Vascular degeneration is a critical pathological process in many human degenerative diseases, which need efficient ways to revascularization. However, little is known about cellular and molecular mechanisms that are used during vascular degeneration and revascularization. Here, we show that Toll-like receptor 2 and 4 (TLR2/4) double deficiency suppressed hyperoxia induced retinal vessel regression in an oxygen-induced retinopathy (OIR) model. Notably, the TLR2/4−/− mice experienced more revascularization after reduced vessel regression compared with wild-type mice, accompanied with less activation of glial cells. Mechanistically, TLR2/4 activation can tip the balance between Th17 cells and regulatory T cells towards Th17 cells, a critical source of the IL-17A. Less migration and infiltration of IL-17A-expressing proinflammatory cells but elevated regulatory T cells were observed in OIR-retinae from TLR2/4−/− mice. Coincidentally, TLR2/4 deficiency suppressed IL-17A production and increased expressions of anti-inflammatory genes. Furthermore, IL-17A promoted activation of glial cells. IL-17A blockade using a neutralizing antibody alleviated retinal cell apoptosis and glial activation in C57/B6-OIR mice, demonstrating the important role of IL-17A pathway in glial function during revascularization. Thus TLR2/4-mediated IL-17A inflammatory signaling is involved in vessel degeneration and revascularization, indicating that modulation of the TLR2/4-IL-17A pathway may be a novel therapeutic strategy for degenerative diseases.