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

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（Age-related macular degeneration, AMD）是一种常见却复杂的视网膜退行性疾病，可导致老年群体出现不可逆的中心性失明。学界普遍认为，其病理进程始于视网膜色素上皮（retinal pigment epithelium, RPE）丢失与光感受器变性。本研究报道了AMD患者黄斑组织中白细胞介素-17A（interleukin-17A, IL17A）及其受体IL17RC的异常表达。体外实验显示，IL17A可诱导RPE细胞死亡，其特征为胞质脂质与自噬体蓄积，并随后激活促凋亡胱天蛋白酶-3（Caspase-3）与胱天蛋白酶-9（Caspase-9）；通过小干扰RNA（siRNA）敲减IL17RC可缓解该病理过程。在局灶性视网膜变性小鼠模型中，依赖IL17的视网膜退行性变可通过编码可溶性IL17受体的腺相关病毒载体进行基因治疗加以预防。该干预手段可通过丝裂原活化蛋白激酶（mitogen-activated protein kinase, MAPK）依赖的通路挽救RPE与光感受器细胞。IL17通路在RPE及光感受器变性中发挥关键作用，有望为AMD的治疗提供潜在靶点。