IL-19调控巨噬细胞M2极化及微血管内皮细胞功能在视网膜新生血管形成中的作用和机制研究

Retinal neovascular disease is a leading cause of blindness worldwide. Many studies showed that cytokines and macrophages participate in regulating neovascularization, M2 macrophages significantly promote progress of neovascular diseases, and interleukin-19 (IL-19) has been reported to promote M2 polarization of macrophages in vivo and in vitro. Our previous studies demonstrated that M2 macrophages enhanced retinal pathological neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Moreover, intravitreal injection of anti-IL-19 antibody remarkably reduced the pathological neovascularization. To further clarify the effects and mechanisms of IL-19 in retinal neovascularization, we plan to use the OIR mouse model and human retinal microvascular endothelial cells, through experimental techniques of cellular and molecular immunology, to investigate the direct effects of IL-19 to retinal microvascular endothelial cells, as well as the indirect effects by regulating M2 polarization of macrophages in retinal neovascularization. We also plan to reveal the immunological mechanisms of IL-19 to retinal pathological neovascularization and physiological revascularization, and to explore the relevance among IL-19, its downstream signal molecules and cytokines, as well as M2 polarization of macrophages and neovascularization, which might provide new molecular targets for treating retinal neovascular disease.

视网膜新生血管性疾病是全球重要的致盲性眼病。众多研究表明，细胞因子及巨噬细胞参与调控新生血管的形成，其中M2型巨噬细胞促进新生血管性疾病的发展，而白细胞介素19(IL-19)可诱导体内外巨噬细胞向M2极化。我们前期研究发现，氧诱导视网膜病变（OIR）小鼠模型中的M2型巨噬细胞可促进视网膜病理性新生血管的形成，玻璃体腔注射抗IL-19抗体可显著抑制其发展。为进一步阐明IL-19在视网膜新生血管形成中的作用及机制，我们将利用OIR小鼠模型和人视网膜微血管内皮细胞，通过细胞和分子免疫学实验技术，探究IL-19对视网膜微血管内皮细胞功能的直接调控作用，及通过调控巨噬细胞M2极化对视网膜新生血管的间接作用，揭示IL-19对视网膜病理性新生血管和生理性血管重构的调控机制，探讨IL-19及其下游信号分子和细胞因子与M2极化和新生血管形成的关联性，为视网膜新生血管性疾病的治疗提供新靶点。

视网膜新生血管性疾病是全球视力损害的重要原因。为探讨IL-19在视网膜新生血管性疾病中的作用及其潜在机制，本项目通过构建OIR小鼠模型，以C57BL/6J野生型（WT）小鼠和IL-19基因敲除（KO）小鼠为研究对象，观察IL-19在视网膜新生血管形成中的作用。通过体内和体外实验，揭示了IL-19通过调控微血管内皮细胞功能和巨噬细胞M2极化在视网膜新生血管形成中的作用和机制。本课题基本按照原计划进行，主要取得了以下进展：1、玻璃体腔注射IL-19重组蛋白（rIL-19）可使视网膜无血管区和病理性新生血管区显著增加，而在IL-19 KO组中，无血管区和病理性新生血管区的面积均受到显著抑制；2、体内外实验表明，IL-19促使巨噬细胞的M2极化，并促进VEGFA和pSTAT3表达；3、IL-19可显著促进人视网膜微血管内皮细胞（HREC）的增殖和迁移；4、玻璃体腔注射rIL-19刺激的骨髓来源的巨噬细胞可增强病理性新生血管，并抑制生理性血管重建。以上结果表明，IL-19通过促进巨噬细胞M2极化和对微血管内皮细胞的直接作用，在视网膜病理性新生血管形成中发挥重要的调控作用。