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P2X7/P2X4 Receptors Mediate Proliferation and Migration of Retinal Microglia in Experimental Glaucoma in Mice
Meng-Xi Xu1, Guo-Li Zhao1, Xin Hu1
1State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
Abstract:
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.
Insights
In glaucoma, microglia proliferation and migration are driven by ATP from Müller cells acting on P2X7R and P2X4R receptors. Blocking these interactions may reduce microglial activity in glaucoma.
Area of Science:
- Ophthalmology
- Neuroscience
- Immunology
Background:
- Microglia play a key role in the inflammatory processes and retinal ganglion cell (RGC) damage observed in glaucoma.
- Understanding the mechanisms regulating microglial behavior is crucial for developing effective glaucoma therapies.
Purpose of the Study:
- To investigate the proliferation and migration of microglia in a mouse model of chronic ocular hypertension (COH).
- To elucidate the specific roles of P2X7 receptor (P2X7R) and P2X4 receptor (P2X4R) in microglial responses in glaucoma.
Main Methods:
- Utilized a mouse model of chronic ocular hypertension (COH) to study microglial behavior in vivo.
- Employed P2X7R and P2X4R blockers (BBG and 5-BDBD, respectively) and knockout models to assess receptor involvement.
- Used primary cultured microglia treated with P2X7R agonist (BzATP) and P2X4R agonist (CTP) to study cellular responses.
- Investigated the involvement of the MEK/ERK signaling pathway in microglial proliferation and migration.
- Analyzed the role of ATP released from Müller cells via connexin43 hemichannels.
Main Results:
- Microglial proliferation in COH retinas was significantly inhibited by P2X7R blockade or knockout.
- P2X7R activation by BzATP induced microglial proliferation and migration, involving the MEK/ERK pathway.
- P2X4R activation by CTP specifically induced microglial migration, which was blocked by 5-BDBD.
- ATP from Müller cells activated P2X7R for proliferation and P2X4R/P2X7R for migration of microglia.
Conclusions:
- Müller cell-derived ATP is a key mediator of microglial proliferation and migration in glaucoma.
- Targeting P2X7R and P2X4R, particularly the interaction between Müller cells and microglia, offers a potential therapeutic strategy for glaucoma.
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