Role of TLR4-MAP4K4 signaling pathway in models of oxygen-induced retinopathy
Role of TLR4-MAP4K4 signaling pathway in models of oxygen-induced retinopathy
复制标题
TLR4-MAP4K4信号通路在氧诱导视网膜病变模型中的作用
DOI：
10.1096/fj.201801086rr
复制
发表时间：
2019-03-01
期刊：
影响因子：
4.8
通讯作者：
Chang, Qing
中科院分区：
文献类型：
--
作者：
Chen, Wenwen;Zhang, Juan;Chang, Qing
早产儿视网膜病变是一种威胁视力的疾病，基于抗VEGF的治疗可能会引起早产儿严重的副作用。视网膜血管生成的机制，特别是独立于VEGF的信号通路，仍然难以捉摸。我们的研究目的是探索TLR4在人视网膜微血管内皮细胞（HRMECs）中介导的信号通路，并研究TLR4拮抗剂在氧诱导视网膜病变（OIR）模型中的作用。我们的研究结果表明，玻璃体内注射TLR4拮抗剂TAK-242减少了OIR小鼠视网膜的非灌注面积，抑制了异常血管生成，并提高了血管密度。抗vegf抗体雷尼单抗进一步增强了这种作用。在培养的hrmes中，TLR4激动剂LPS上调TLR4/MAPKK激酶激酶4 （MAP4K4）信号，促进细胞增殖和迁移，降低细胞的屏障功能。MAP4K4在hrmes中的下调可消除LPS的促血管生成作用。我们的数据表明，TLR4-MAP4K4通路可以通过独立于VEGF的机制调节视网膜新生血管。陈伟，张军，张鹏，胡峰，蒋天，顾军，常青。TLR4-MAP4K4信号通路在氧致视网膜病变模型中的作用。
Retinopathy of prematurity is a vision-threatening condition, and therapies based on antagonizing VEGF may elicit serious side effects in premature infants. Mechanisms of retinal angiogenesis, particularly the signaling pathways independent of VEGF, remain elusive. The goals of our study were to explore TLR4-mediated signaling pathways in human retinal microvascular endothelial cells (HRMECs) and to examine the effects of TLR4 antagonists in models of oxygen-induced retinopathy (OIR). Our results show that intravitreal injection of the TLR4 antagonist TAK-242 reduced areas of nonperfusion, inhibited aberrant angiogenesis, and improved vascular density in the retina of OIR mice. The effects were further potentiated by the anti-VEGF antibody ranibizumab. In cultured HRMECs, the TLR4 agonist LPS up-regulated TLR4/MAPKK kinase kinase 4 (MAP4K4) signaling, and promoted cell proliferation and migration, and reduced barrier functions of the cells. Down-regulation of MAP4K4 in HRMECs abolished the proangiogenic effects by LPS. Our data suggest that the TLR4-MAP4K4 pathway can regulate retinal neovascularization via mechanisms independent of VEGF.Chen, W., Zhang, J., Zhang, P., Hu, F., Jiang, T., Gu, J., Chang, Q. Role of TLR4-MAP4K4 signaling pathway in models of oxygen-induced retinopathy.