Microglia-Neutrophil Interactions Drive Dry AMD-like Pathology in a Mouse Model.
Microglia-Neutrophil Interactions Drive Dry AMD-like Pathology in a Mouse Model.
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在干性年龄相关性黄斑变性（AMD）中，炎症在疾病发病机制中起着关键作用。小胶质细胞和中性粒细胞等先天免疫细胞浸润视网膜下腔 (SRS)，诱发慢性炎症和 AMD 进展。但我们理解的一个主要差距是这些细胞在 AMD 中如何相互作用。在这里，我们报告了一个关于小胶质细胞和中性粒细胞之间的动态相互作用如何促进 AMD 病理学的新概念。使用充分表征的基因工程小鼠模型作为工具，我们发现在患病状态下，视网膜色素上皮（RPE）细胞触发小胶质细胞中的促炎（M1）转变，同时稳态标记物CX3CR1的表达减少。激活的小胶质细胞定位于 SRS 并调节局部中性粒细胞功能，触发其激活，从而诱导早期 RPE 变化。配体受体 (LR) 环分析和细胞培养研究表明，M1 小胶质细胞还通过与小胶质细胞上的 CD14 相互作用来诱导中性粒细胞粘附介质（整合素 β1/α4）的表达。此外，抑制小胶质细胞中的 Akt2 可以减轻小胶质细胞诱导的中性粒细胞激活和随后的中性粒细胞介导的 RPE 改变。这些结果表明，小胶质细胞中的 Akt2 通路驱动 M1 小胶质细胞介导的中性粒细胞激活，从而引发早期 RPE 变性，并且是早期 AMD（没有治疗选择的阶段）的新治疗靶点。
In dry age-related macular degeneration (AMD), inflammation plays a key role in disease pathogenesis. Innate immune cells such as microglia and neutrophils infiltrate the sub-retinal space (SRS) to induce chronic inflammation and AMD progression. But a major gap in our understanding is how these cells interact with each other in AMD. Here, we report a novel concept of how dynamic interactions between microglia and neutrophils contribute to AMD pathology. Using well-characterized genetically engineered mouse models as tools, we show that in the diseased state, retinal pigmented epithelial (RPE) cells trigger pro-inflammatory (M1) transition in microglia with diminished expression of the homeostatic marker, CX3CR1. Activated microglia localize to the SRS and regulate local neutrophil function, triggering their activation and thereby inducing early RPE changes. Ligand receptor (LR)-loop analysis and cell culture studies revealed that M1 microglia also induce the expression of neutrophil adhesion mediators (integrin β1/α4) through their interaction with CD14 on microglia. Furthermore, microglia-induced neutrophil activation and subsequent neutrophil-mediated RPE alterations were mitigated by inhibiting Akt2 in microglia. These results suggest that the Akt2 pathway in microglia drives M1 microglia-mediated neutrophil activation, thereby triggering early RPE degeneration and is a novel therapeutic target for early AMD, a stage without treatment options.