作为细胞因子阻断剂的可溶性白细胞介素-17受体基因转移可预防白细胞介素-17视网膜毒性：对年龄相关性黄斑变性的意义
Interleukin-17 retinotoxicity is prevented by gene transfer of a soluble interleukin-17 receptor acting as a cytokine blocker: implications for age-related macular degeneration.
作者信息
Ardeljan Daniel, Wang Yujuan, Park Stanley, Shen Defen, Chu Xi Kathy, Yu Cheng-Rong, Abu-Asab Mones, Tuo Jingsheng, Eberhart Charles G, Olsen Timothy W, Mullins Robert F, White Gary, Wadsworth Sam, Scaria Abraham, Chan Chi-Chao
机构信息
Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America; School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America; Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
出版信息
PLoS One. 2014 Apr 29;9(4):e95900. doi: 10.1371/journal.pone.0095900. eCollection 2014.
Age-related macular degeneration (AMD) is a common yet complex retinal degeneration that causes irreversible central blindness in the elderly. Pathology is widely believed to follow loss of retinal pigment epithelium (RPE) and photoreceptor degeneration. Here we report aberrant expression of interleukin-17A (IL17A) and the receptor IL17RC in the macula of AMD patients. In vitro, IL17A induces RPE cell death characterized by the accumulation of cytoplasmic lipids and autophagosomes with subsequent activation of pro-apoptotic Caspase-3 and Caspase-9. This pathology is reduced by siRNA knockdown of IL17RC. IL17-dependent retinal degeneration in a mouse model of focal retinal degeneration can be prevented by gene therapy with adeno-associated virus vector encoding soluble IL17 receptor. This intervention rescues RPE and photoreceptors in a MAPK-dependent process. The IL17 pathway plays a key role in RPE and photoreceptor degeneration and could hold therapeutic potential in AMD.
年龄相关性黄斑变性（AMD）是一种常见但复杂的视网膜变性疾病，可导致老年人不可逆的中心视力丧失。普遍认为其病理过程是视网膜色素上皮（RPE）丧失和光感受器变性。在此，我们报告了白细胞介素-17A（IL17A）及其受体IL17RC在AMD患者黄斑区的异常表达。在体外，IL17A诱导RPE细胞死亡，其特征为细胞质脂质和自噬体积累，随后促凋亡的半胱天冬酶-3和半胱天冬酶-9被激活。通过IL17RC的小干扰RNA敲低可减轻这种病理变化。在局灶性视网膜变性小鼠模型中，编码可溶性IL17受体的腺相关病毒载体基因疗法可预防IL17依赖性视网膜变性。该干预措施通过依赖丝裂原活化蛋白激酶（MAPK）信号通路挽救RPE和光感受器。IL17信号通路在RPE和光感受器变性中起关键作用，在AMD中可能具有治疗潜力。
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