Sorbonne Université, INSERM, CNRS, UMR_S 968, Institut de la Vision, 75012, Paris, France.
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Experimental Ophthalmology, Department of Ophthalmology, Charitéplatz 1, 10117, Berlin, Germany.
J Neuroinflammation. 2024 Jan 17;21(1):22. doi: 10.1186/s12974-024-03011-z.
Age-related macular degeneration (AMD) is invariably associated with the chronic accumulation of activated mononuclear phagocytes in the subretinal space. The mononuclear phagocytes are composed of microglial cells but also of monocyte-derived cells, which promote photoreceptor degeneration and choroidal neovascularization. Infiltrating blood monocytes can originate directly from bone marrow, but also from a splenic reservoir, where bone marrow monocytes develop into angiotensin II receptor (ATR1) splenic monocytes. The involvement of splenic monocytes in neurodegenerative diseases such as AMD is not well understood. Using acute inflammatory and well-phenotyped AMD models, we demonstrate that angiotensin II mobilizes ATR1 splenic monocytes, which we show are defined by a transcriptional signature using single-cell RNA sequencing and differ functionally from bone marrow monocytes. Splenic monocytes participate in the chorio-retinal infiltration and their inhibition by ATR1 antagonist and splenectomy reduces the subretinal mononuclear phagocyte accumulation and pathological choroidal neovascularization formation. In aged AMD-risk ApoE2-expressing mice, a chronic AMD model, ATR1 antagonist and splenectomy also inhibit the chronic retinal inflammation and associated cone degeneration that characterizes these mice. Our observation of elevated levels of plasma angiotensin II in AMD patients, suggests that similar events take place in clinical disease and argue for the therapeutic potential of ATR1 antagonists to inhibit splenic monocytes for the treatment of blinding AMD.
年龄相关性黄斑变性（AMD）总是与视网膜下空间中活化的单核吞噬细胞的慢性积累有关。单核吞噬细胞由小胶质细胞组成，但也由单核细胞衍生的细胞组成，这些细胞促进光感受器变性和脉络膜新生血管形成。浸润的血液单核细胞可以直接来源于骨髓，也可以来源于脾脏储备库，骨髓单核细胞在那里发育为血管紧张素 II 受体（ATR1）脾脏单核细胞。脾脏单核细胞在 AMD 等神经退行性疾病中的作用尚不清楚。使用急性炎症和表型良好的 AMD 模型，我们证明血管紧张素 II 动员 ATR1 脾脏单核细胞，我们使用单细胞 RNA 测序显示其具有转录特征，并且与骨髓单核细胞在功能上不同。脾脏单核细胞参与脉络膜视网膜浸润，ATR1 拮抗剂和脾切除术抑制其下视网膜单核吞噬细胞的积累和病理性脉络膜新生血管形成。在年龄相关性黄斑变性风险 ApoE2 表达小鼠，即慢性 AMD 模型中，ATR1 拮抗剂和脾切除术也抑制了这些小鼠的慢性视网膜炎症和相关的锥体变性。我们观察到 AMD 患者血浆血管紧张素 II 水平升高，表明在临床疾病中也发生了类似的事件，并为 ATR1 拮抗剂抑制脾脏单核细胞治疗致盲 AMD 的治疗潜力提供了依据。
