Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan.
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
JCI Insight. 2018 Sep 20;3(18). doi: 10.1172/jci.insight.96902.
Age-related macular degeneration (AMD), a progressive chronic disease of the central retina, is associated with aging and is a leading cause of blindness worldwide. Here, we demonstrate that leukotriene B4 (LTB4) receptor 1 (BLT1) promotes laser-induced choroidal neovascularization (CNV) in a mouse model for wet-type AMD. CNV was significantly less in BLT1-deficient (BLT1-KO) mice compared with BLT1-WT controls. Expression of several proangiogenic and profibrotic factors was lower in BLT1-KO eyes than in BLT1-WT eyes. LTB4 production in the eyes was substantially increased in the early phase after laser injury. BLT1 was highly expressed in M2 macrophages in vitro and in vivo, and ocular BLT1+ M2 macrophages were increased in the aged eyes after laser injury. Furthermore, M2 macrophages were rapidly attracted by LTB4 and subsequently produced VEGF-A- through BLT1-mediated signaling. Consequently, intravitreal injection of M2 macrophages augmented CNV formation, which was attenuated by BLT1 deficiency. Thus, laser-induced injury to the retina triggered LTB4 production and attracted M2 macrophages via BLT1, leading to development of CNV. A selective BLT1 antagonist (CP105696) and 3 LTB4 inhibitors (zileuton, MK-886, and bestatin) reduced CNV in a dose-dependent manner. CP105696 also inhibited the accumulation of BLT1+ M2 macrophages in the laser-injured eyes of aged mice. Together, these results indicate that the LTB4-BLT1 axis is a potentially novel therapeutic target for CNV of wet-type AMD.
年龄相关性黄斑变性（AMD）是一种与年龄相关的进行性慢性中心性视网膜疾病，是全球致盲的主要原因。在这里，我们证明白三烯 B4（LTB4）受体 1（BLT1）在湿性 AMD 的小鼠模型中促进激光诱导脉络膜新生血管（CNV）。与 BLT1-WT 对照相比，BLT1 缺陷（BLT1-KO）小鼠的 CNV 明显减少。BLT1-KO 眼的几种促血管生成和促纤维化因子的表达低于 BLT1-WT 眼。激光损伤后早期眼部 LTB4 产量显著增加。BLT1 在体外和体内 M2 巨噬细胞中高度表达，激光损伤后老年眼的眼内 BLT1+M2 巨噬细胞增加。此外，LTB4 迅速吸引 M2 巨噬细胞，随后通过 BLT1 介导的信号通路产生 VEGF-A。因此，玻璃体腔注射 M2 巨噬细胞可增强 CNV 形成，而 BLT1 缺乏可减弱这种作用。因此，视网膜激光损伤触发 LTB4 产生，并通过 BLT1 吸引 M2 巨噬细胞，导致 CNV 发生。一种选择性 BLT1 拮抗剂（CP105696）和 3 种 LTB4 抑制剂（齐留通、MK-886 和贝斯特atin）以剂量依赖性方式减少 CNV。CP105696 还抑制了老年小鼠激光损伤眼中 BLT1+M2 巨噬细胞的积累。综上所述，这些结果表明 LTB4-BLT1 轴可能是湿性 AMD 中 CNV 的一个潜在的新治疗靶点。
