Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
Vascular Microenvironment Laboratory, Department of Pharmacology and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
Glia. 2019 Feb;67(2):321-331. doi: 10.1002/glia.23542. Epub 2018 Nov 16.
Inner and outer blood-retinal barriers (BRBs), mainly composed of retinal endothelial cells and retinal pigment epithelial (RPE) cells, respectively, maintain the integrity of the retinal tissues. In this study, we aimed to investigate the mechanisms of the outer BRB disruption regarding the interaction between RPE and microglia. In mice with high-fat diet-induced obesity and streptozotocin-induced hyperglycemia, microglia accumulated on the RPE layer, as in those after intravitreal injection of interleukin (IL)-6, which is elevated in ocular fluids of patients with diabetic retinopathy. Although IL-6 did not directly affect the levels of zonula occludens (ZO)-1 and occludin in RPE cells, IL-6 increased VEGFA mRNA in RPE cells to recruit microglial cells. In microglial cells, IL-6 upregulated the mRNA levels of MCP1, MIP1A, and MIP1B, to amplify the recruitment of microglial cells. In this manner, IL-6 modulated RPE and microglial cells to attract microglial cells on RPE cells. Furthermore, IL-6-treated microglial cells produced and secreted tumor necrosis factor (TNF)-α, which activated NF-κB and decreased the levels of ZO-1 in RPE cells. As STAT3 inhibition reversed the effects of IL-6-treated microglial cells on the RPE monolayer in vitro, it reduced the recruitment of microglial cells and the production of TNF-α in RPE tissues in streptozotocin-treated mice. Taken together, IL-6-treated RPE and microglial cells amplified the recruitment of microglial cells and IL-6-treated microglial cells produced TNF-α to disrupt the outer BRB in diabetic retinopathy.
内、外血视网膜屏障（BRB）分别主要由视网膜内皮细胞和视网膜色素上皮（RPE）细胞组成，维持视网膜组织的完整性。在这项研究中，我们旨在研究 RPE 与小胶质细胞相互作用时，外 BRB 破坏的机制。在高脂肪饮食诱导肥胖和链脲佐菌素诱导高血糖的小鼠中，小胶质细胞在 RPE 层上聚集，就像在眼内注射白细胞介素（IL）-6 后一样，IL-6 在糖尿病视网膜病变患者的眼液中升高。虽然 IL-6 不会直接影响 RPE 细胞中紧密连接蛋白（ZO）-1 和封闭蛋白的水平，但 IL-6 增加了 RPE 细胞中 VEGFA mRNA 的水平，以募集小胶质细胞。在小胶质细胞中，IL-6 上调了 MCP1、MIP1A 和 MIP1B 的 mRNA 水平，以放大小胶质细胞的募集。通过这种方式，IL-6 调节 RPE 和小胶质细胞以吸引小胶质细胞在 RPE 细胞上。此外，IL-6 处理的小胶质细胞产生和分泌肿瘤坏死因子（TNF）-α，激活 NF-κB 并降低 RPE 细胞中 ZO-1 的水平。由于 STAT3 抑制逆转了 IL-6 处理的小胶质细胞对体外 RPE 单层的作用，它减少了小胶质细胞在链脲佐菌素处理的小鼠中的募集和 RPE 组织中 TNF-α的产生。总之，IL-6 处理的 RPE 和小胶质细胞放大了小胶质细胞的募集，并且 IL-6 处理的小胶质细胞产生 TNF-α以破坏糖尿病视网膜病变中的外 BRB。
