Retinal microglia are critical for subretinal neovascular formation.
Retinal microglia are critical for subretinal neovascular formation.
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DOI：
10.1172/jci.insight.137317
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发表时间：
2020-05
期刊：
影响因子：
8
通讯作者：
Ayumi Usui‐Ouchi;Y. Usui;T. Kurihara;E. Aguilar;Michael I. Dorrell;Yoichiro Ideguchi;S. Sakimoto
中科院分区：
文献类型：
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作者：
Ayumi Usui‐Ouchi;Y. Usui;T. Kurihara;E. Aguilar;Michael I. Dorrell;Yoichiro Ideguchi;S. Sakimoto
视网膜下异常新生血管是威胁视力的视网膜疾病的特征，包括黄斑毛细血管扩张(Mactel)和视网膜血管瘤样增生(RAP)。在极低密度脂蛋白受体突变小鼠(Vldlr-/-)中观察到视网膜下新生血管簇和光感受器功能障碍。这些变化反映了在Mactel和RAP患者中观察到的变化，但其发病机制很大程度上尚不清楚。在这项研究中，我们发现视网膜小胶质细胞与Vldlr-/-小鼠的视网膜新生血管簇和黄斑患者的视网膜组织密切相关；根据视网膜电图术的评估，切除小胶质细胞/巨噬细胞显著地防止了视网膜新生血管簇的形成，并改善了神经元功能。VMD2驱动的视网膜色素上皮(RPE)特异性的VEGF基因敲除大大减少了小胶质细胞/巨噬细胞在视网膜下的渗透，从而减少了NV簇。这些发现突出了小胶质细胞/巨噬细胞在NV发病机制中的作用，为黄斑和RAP患者视网膜下新生血管的潜在致病细胞机制提供了有价值的线索，并提示靶向小胶质细胞激活可能是这些疾病的一种治疗选择。
Abnormal subretinal neovascularization is characteristic of vision-threatening retinal diseases including macular telangiectasia (MacTel) and retinal angiomatous proliferation (RAP). Subretinal neovascular tufts and photoreceptor dysfunction are observed in very low-density lipoprotein receptor mutant mice (Vldlr-/-). These changes mirror those observed in MacTel and RAP patients, but the pathogenesis is largely unknown. In this study, we show that retinal microglia are closely associated with retinal neovascular tufts in Vldlr-/- mice and retinal tissue from MacTel patients; ablation of microglia/macrophages dramatically prevents formation of retinal neovascular tufts and improves neuronal function as assessed by electroretinography. VMD2-driven retinal pigmented epithelium (RPE)-specific knockouts of VEGF greatly reduced subretinal infiltration of microglia/macrophages, subsequently reducing NV tufts. These findings highlight the contribution of microglia/macrophages to the pathogenesis of NV, provide valuable clues regarding potential causative cellular mechanisms for subretinal neovascularization in MacTel and RAP patients, and suggest that targeting microglia activation may be a therapeutic option in these diseases.