{"title":"二甲胺四环素治疗减少单核吞噬细胞的活化和改善视网膜功能的小鼠模型先天性黑朦。","authors":"Ettel Bubis, Ifat Sher, Hadas Ketter-Katz, Estela Derzane, Florian Sennlaub, Ygal Rotenstreich","doi":"10.1007/s00417-025-06768-y","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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<sup>2</sup> and 33.1 ± 8 cell/mm<sup>2</sup> in the central and peripheral retina, respectively. Minocycline treatment significantly reduced MP density in the peripheral subretina (16.2 ± 1.8 MP cell/mm<sup>2</sup>) compared with mice treated with PBS (27.2 ± 2.4 MP cell/mm<sup>2</sup>, 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).</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":520634,"journal":{"name":"Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Minocycline treatment reduces the activation of mononuclear phagocytes and improves retinal function in a mouse model of Leber congenital amaurosis.\",\"authors\":\"Ettel Bubis, Ifat Sher, Hadas Ketter-Katz, Estela Derzane, Florian Sennlaub, Ygal Rotenstreich\",\"doi\":\"10.1007/s00417-025-06768-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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<sup>2</sup> and 33.1 ± 8 cell/mm<sup>2</sup> in the central and peripheral retina, respectively. Minocycline treatment significantly reduced MP density in the peripheral subretina (16.2 ± 1.8 MP cell/mm<sup>2</sup>) compared with mice treated with PBS (27.2 ± 2.4 MP cell/mm<sup>2</sup>, 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).</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":520634,\"journal\":{\"name\":\"Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-06-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1007/s00417-025-06768-y\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1007/s00417-025-06768-y","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
目的：莱伯先天性黑朦（Leber congenital amaurosis， LCA）是一种严重的遗传性视网膜变性，以早发性视力丧失为特征。在RPE65/rd12 LCA小鼠模型中，我们旨在表征视网膜单核吞噬细胞（MP）活化与视网膜变性之间的关系。方法：RPE65/rd12野生型小鼠39只，C57BL/6J野生型小鼠10只。RPE65/rd12小鼠从出生后第28天开始，每天腹腔注射米诺环素（5 mg/kg），持续8周（P28）。采用脉络膜-视网膜色素上皮（RPE）平片法检测视网膜下MP细胞密度，视网膜电图（ERG）检测视网膜功能。结果：野生型C57BL/6J小鼠在p28 ~ p84岁时，MPs仅位于视网膜内层。相比之下，在RPE65/rd12小鼠中，MPs早在P56时就以中央到外周的梯度迁移到视网膜下。P84时，视网膜下MPs的密度增加了近3倍，在视网膜中央和周围分别达到61.3±6.2 cells /mm2和33.1±8 cell/mm2。米诺环素治疗显著降低视网膜下周MP密度（16.2±1.8 MP细胞/mm2），而PBS治疗小鼠（27.2±2.4 MP细胞/mm2， p = 0.006）。在光适应条件下，米诺环素组的最大视网膜电图b波反应明显高于pbs组（平均±SE: 199µv±28µv vs. 129.8µv±9.8µv, p = 0.016）。结论：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向视网膜下的迁移与视网膜功能的改善有关。这些发现可能指导针对MP激活的LCA和潜在的其他类视黄醇周期相关的视网膜变性致盲疾病的神经保护疗法的发展。
Minocycline treatment reduces the activation of mononuclear phagocytes and improves retinal function in a mouse model of Leber congenital amaurosis.
Purpose: 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.
Methods: 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).
Results: 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/mm2 and 33.1 ± 8 cell/mm2 in the central and peripheral retina, respectively. Minocycline treatment significantly reduced MP density in the peripheral subretina (16.2 ± 1.8 MP cell/mm2) compared with mice treated with PBS (27.2 ± 2.4 MP cell/mm2, 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).
Conclusions: 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.
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