Wang Tan, Song Ying, Bell Brent A, Anderson Brandon D, Lee Timothy T, Yu Weihong, Dunaief Joshua L
Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China; FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
Exp Eye Res. 2025 Jan;250:110161. doi: 10.1016/j.exer.2024.110161. Epub 2024 Nov 16.
Complement factor 3 (C3) has emerged as a primary therapeutic target in age-related macular degeneration (AMD) supported by genetic, histologic, and clinical trial evidence. Yet, the site(s) of action are unclear. The purpose of this study was to test the effect of C3 knockout on photoreceptors and retinal pigment epithelial cells (RPE) in the sodium iodate (NaIO) model, which mirrors some features of AMD. C3 and WT mice, both on a C57Bl/6J background, were injected intraperitoneally with 25 mg/kg NaIO. Electroretinography and optical coherence tomography were performed 7 days later to assess retinal function and structure, respectively. Then, mice were euthanized for retinal immunohistochemistry, quantitative real-time PCR and enzyme-linked immunosorbent assays. NaIO increased C3 protein levels in the neural retina but not RPE. WT but not C3 mice showed NaIO-induced iC3b deposition on photoreceptor outer segments. C3 mice were partially protected against photoreceptor layer thinning. There was partial preservation of rod and cone function in the C3 group. Neither RPE structure nor function was protected. These results suggest outer segment opsonization contributes to photoreceptor death in this model, and that targeting C3 can protect photoreceptor structure and function when RPE cells are stressed.
补体因子3（C3）已成为年龄相关性黄斑变性（AMD）的主要治疗靶点，这一观点得到了遗传学、组织学和临床试验证据的支持。然而，其作用位点尚不清楚。本研究的目的是在碘酸钠（NaIO）模型中测试C3基因敲除对光感受器和视网膜色素上皮细胞（RPE）的影响，该模型反映了AMD的一些特征。将C57Bl/6J背景的C3基因敲除小鼠和野生型（WT）小鼠腹腔注射25mg/kg NaIO。7天后分别进行视网膜电图和光学相干断层扫描，以评估视网膜功能和结构。然后，对小鼠实施安乐死以进行视网膜免疫组织化学、定量实时聚合酶链反应和酶联免疫吸附测定。NaIO可增加神经视网膜而非RPE中的C3蛋白水平。WT小鼠而非C3基因敲除小鼠在光感受器外节上出现NaIO诱导的iC3b沉积。C3基因敲除小鼠的光感受器层变薄得到部分保护。C3组的视杆和视锥功能有部分保留。RPE的结构和功能均未得到保护。这些结果表明，在该模型中，外节调理作用导致光感受器死亡，并且当RPE细胞受到应激时，靶向C3可保护光感受器的结构和功能。
