State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
Institute of Neuroscience and Third Affiliated Hospital, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450003, China.
Neurosci Bull. 2022 Aug;38(8):901-915. doi: 10.1007/s12264-022-00833-w. Epub 2022 Mar 7.
Microglia are involved in the inflammatory response and retinal ganglion cell damage in glaucoma. Here, we investigated how microglia proliferate and migrate in a mouse model of chronic ocular hypertension (COH). In COH retinas, the microglial proliferation that occurred was inhibited by the P2X7 receptor (P2X7R) blocker BBG or P2X7R knockout, but not by the P2X4R blocker 5-BDBD. Treatment of primary cultured microglia with BzATP, a P2X7R agonist, mimicked the effects of cell proliferation and migration in COH retinas through the intracellular MEK/ERK signaling pathway. Transwell migration assays showed that the P2X4R agonist CTP induced microglial migration, which was completely blocked by 5-BDBD. In vivo and in vitro experiments demonstrated that ATP, released from activated Müller cells through connexin43 hemichannels, acted on P2X7R to induce microglial proliferation, and acted on P2X4R/P2X7R (mainly P2X4R) to induce microglial migration. Our results suggest that inhibiting the interaction of Müller cells and microglia may attenuate microglial proliferation and migration in glaucoma.
小胶质细胞参与青光眼的炎症反应和视网膜神经节细胞损伤。在这里，我们研究了小胶质细胞在慢性眼压升高（COH）小鼠模型中如何增殖和迁移。在 COH 视网膜中，P2X7 受体（P2X7R）阻滞剂 BBG 或 P2X7R 敲除抑制了小胶质细胞的增殖，但 P2X4R 阻滞剂 5-BDBD 则没有。用 P2X7R 激动剂 BzATP 处理原代培养的小胶质细胞，通过细胞内 MEK/ERK 信号通路模拟了 COH 视网膜中细胞增殖和迁移的作用。Transwell 迁移实验表明，P2X4R 激动剂 CTP 诱导小胶质细胞迁移，5-BDBD 完全阻断了这一作用。体内和体外实验表明，通过缝隙连接蛋白 43 半通道从激活的 Müller 细胞释放的 ATP 通过 P2X7R 作用于小胶质细胞，诱导小胶质细胞增殖，通过 P2X4R/P2X7R（主要是 P2X4R）诱导小胶质细胞迁移。我们的结果表明，抑制 Müller 细胞和小胶质细胞的相互作用可能减轻青光眼中小胶质细胞的增殖和迁移。
