Departments of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States of America ; Second Hospital of Jilin University, Changchun, Jilin Province, P.R. China.
Departments of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States of America ; James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, United States of America.
PLoS One. 2014 Jan 28;9(1):e87530. doi: 10.1371/journal.pone.0087530. eCollection 2014.
Choroidal neovascularization (CNV) is aberrant angiogenesis associated with exudative age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Inflammation has been suggested as a risk factor for AMD. The IKK2/NF-κB pathway plays a key role in the inflammatory response through regulation of the transcription of cytokines, chemokines, growth factors and angiogenic factors. We investigated the functional role of IKK2 in development of the laser-induced CNV using either Ikk2 conditional knockout mice or an IKK2 inhibitor. The retinal neuronal tissue and RPE deletion of IKK2 was generated by breeding Ikk2(-/flox) mice with Nestin-Cre mice. Deletion of Ikk2 in the retina caused no obvious defect in retinal development or function, but resulted in a significant reduction in laser-induced CNV. In addition, intravitreal or retrobulbar injection of an IKK2 specific chemical inhibitor, TPCA-1, also showed similar inhibition of CNV. Furthermore, in vitro inhibition of IKK2 in ARPE-19 cells significantly reduced heat shock-induced expression of NFKBIA, IL1B, CCL2, VEGFA, PDGFA, HIF1A, and MMP-2, suggesting that IKK2 may regulate multiple molecular pathways involved in laser-induced CNV. The in vivo laser-induced expression of VEGFA, and HIF1A in RPE and choroidal tissue was also blocked by TPCA-1 treatment. Thus, IKK2/NF-κB signaling appears responsible for production of pro-inflammatory and pro-angiogenic factors in laser-induced CNV, suggesting that this intracellular pathway may serve as an important therapeutic target for aberrant angiogenesis in exudative AMD.
脉络膜新生血管（CNV）是与渗出性年龄相关性黄斑变性（AMD）相关的异常血管生成，是老年人失明的主要原因。炎症被认为是 AMD 的一个危险因素。IKK2/NF-κB 途径通过调节细胞因子、趋化因子、生长因子和血管生成因子的转录，在炎症反应中发挥关键作用。我们使用 IKK2 条件性敲除小鼠或 IKK2 抑制剂研究了 IKK2 在激光诱导的 CNV 发展中的功能作用。通过将 Ikk2(-/flox) 小鼠与 Nestin-Cre 小鼠杂交，生成视网膜神经元组织和 RPE 中的 IKK2 缺失。视网膜中 IKK2 的缺失不会导致视网膜发育或功能明显缺陷，但会导致激光诱导的 CNV 显著减少。此外，玻璃体内或球后注射 IKK2 特异性化学抑制剂 TPCA-1 也显示出对 CNV 的类似抑制作用。此外，在 ARPE-19 细胞中抑制 IKK2 在体外显著降低了热休克诱导的 NFKBIA、IL1B、CCL2、VEGFA、PDGFA、HIF1A 和 MMP-2 的表达，表明 IKK2 可能调节参与激光诱导的 CNV 的多个分子途径。TPCA-1 处理还阻断了体内激光诱导的 RPE 和脉络膜组织中 VEGFA 和 HIF1A 的表达。因此，IKK2/NF-κB 信号似乎负责激光诱导的 CNV 中促炎和促血管生成因子的产生，表明该细胞内途径可能是渗出性 AMD 中异常血管生成的重要治疗靶点。
