Bubis Ettel, Sher Ifat, Ketter-Katz Hadas, Derzane Estela, Sennlaub Florian, Rotenstreich Ygal
Goldschleger Eye Institute, Sheba Medical Center, Tel-Hashomer, 5262100, Israel.
Ophthalmology Department, Faculty of Medical and Health Sciences, Tel-Aviv University, Tel Aviv, 6997801, Israel.
Graefes Arch Clin Exp Ophthalmol. 2025 Jun 18. doi: 10.1007/s00417-025-06768-y.
Leber congenital amaurosis (LCA) is a severe hereditary retinal degeneration characterized by early-onset vision loss. Here, we aimed to characterize the association between retinal mononuclear phagocyte (MP) activation and retinal degeneration in the RPE65/rd12 mouse model of LCA.
Thirty-nine RPE65/rd12 and ten C57BL/6J wild-type mice were used. RPE65/rd12 mice were treated with minocycline by daily intraperitoneal injection (5 mg/kg) for eight weeks starting at age postnatal day 28 (P28). MP cell density in the subretina was determined by choroid-retinal pigment epithelium (RPE) flat mount analysis, and retinal function was determined by electroretinogram (ERG).
In wild-type C57BL/6J mice, MPs were exclusively located in the inner retinal layers at ages P28-P84. By contrast, in the RPE65/rd12 mice, MPs migrated into the subretina as early as P56 in a central-to-peripheral gradient. By P84, the density of MPs in the subretina increased by nearly 3-fold, reaching 61.3 ± 6.2 cell/mm and 33.1 ± 8 cell/mm in the central and peripheral retina, respectively. Minocycline treatment significantly reduced MP density in the peripheral subretina (16.2 ± 1.8 MP cell/mm) compared with mice treated with PBS (27.2 ± 2.4 MP cell/mm, respectively, p = 0.006). Maximal electroretinogram b-wave responses were significantly higher in minocycline- vs. PBS-treated mice under light-adapted conditions following eight weeks of treatment (mean ± SE: 199µv ± 28µv vs. 129.8µv ± 9.8µv, p = 0.016).
Our data indicates that MP migration into the subretina is associated with retinal degeneration in RPE65/rd12 mice. Inhibiting MP migration into the subretina was associated with improved retinal function. These findings may guide the development of therapies targeting MP activation for neuroprotection in LCA and potentially other retinoid cycle-related retinal degeneration blinding diseases.
莱伯先天性黑蒙（LCA）是一种严重的遗传性视网膜变性，其特征为早发性视力丧失。在此，我们旨在描述视网膜单核吞噬细胞（MP）激活与LCA的RPE65/rd12小鼠模型中视网膜变性之间的关联。
使用39只RPE65/rd12小鼠和10只C57BL/6J野生型小鼠。从出生后第28天（P28）开始，对RPE65/rd12小鼠每日腹腔注射米诺环素（5mg/kg），持续8周。通过脉络膜-视网膜色素上皮（RPE）平铺分析确定视网膜下MP细胞密度，并通过视网膜电图（ERG）测定视网膜功能。
在野生型C57BL/6J小鼠中，P28 - P84年龄段时，MP仅位于视网膜内层。相比之下，在RPE65/rd12小鼠中，MP最早在P56时以从中央到周边的梯度迁移到视网膜下。到P84时，视网膜下MP密度增加了近3倍，在中央和周边视网膜分别达到61.3±6.2个细胞/mm和33.1±8个细胞/mm。与用磷酸盐缓冲盐水（PBS）处理的小鼠相比，米诺环素处理显著降低了周边视网膜下的MP密度（分别为16.2±1.8个MP细胞/mm和27.2±2.4个MP细胞/mm，p = 0.006）。治疗8周后，在明适应条件下，米诺环素处理的小鼠的最大视网膜电图b波反应显著高于PBS处理的小鼠（平均值±标准误：199μv±28μv对129.8μv±9.8μv，p = 0.016）。
我们的数据表明，MP迁移到视网膜下与RPE65/rd12小鼠的视网膜变性有关。抑制MP迁移到视网膜下与视网膜功能改善有关。这些发现可能指导针对MP激活的疗法的开发，用于LCA以及可能其他与视黄醛循环相关的视网膜变性致盲疾病的神经保护。
