P2X7/P2X4 Receptors Mediate Proliferation and Migration of Retinal Microglia in Experimental Glaucoma in Mice

Meng-Xi Xu1 • Guo-Li Zhao1 • Xin Hu1 • Han Zhou1 • Shu-Ying Li1 • Fang Li1 • Yanying Miao1 • Bo Lei2 • Zhongfeng Wang1

1 State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China

2 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



    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 Mu¨ller 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 Mu¨ller cells and microglia may attenuate microglial proliferation and migration in glaucoma.




    Glaucoma; Chronic ocular hypertension;Retinal microglia; Proliferation; Migration; P2X7R/P2X4R; Müller cells