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

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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.

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Acknowledgments

We thanks Dr. Xiong-Li Yang for helpful discussion and critical comments on the manuscript. This work was supported by grants from the National Natural Science Foundation of China (81790642 and 31872765), the Shanghai Municipal Science and Technology Major Project (2018SHZDZX01), ZJ Lab, and the Shanghai Center for Brain Science and Brain-Inspired Technology.

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

    Meng-Xi Xu, Guo-Li Zhao, Xin Hu, Han Zhou, Shu-Ying Li, Fang Li, Yanying Miao & Zhongfeng Wang

  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

    Bo Lei

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  1. Meng-Xi Xu
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Xu, MX., Zhao, GL., Hu, X. et al. P2X7/P2X4 Receptors Mediate Proliferation and Migration of Retinal Microglia in Experimental Glaucoma in Mice. Neurosci. Bull. 38, 901–915 (2022). https://doi.org/10.1007/s12264-022-00833-w

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