@article{80a19fc624f8439e93fc44355088847c,
title = "Microglial P2Y6 calcium signaling promotes phagocytosis and shapes neuroimmune responses in epileptogenesis",
abstract = "Microglial calcium signaling is rare in a baseline state but strongly engaged during early epilepsy development. The mechanism(s) governing microglial calcium signaling are not known. By developing an in vivo uridine diphosphate (UDP) fluorescent sensor, GRABUDP1.0, we discovered that UDP release is a conserved response to seizures and excitotoxicity across brain regions. UDP can signal through the microglial-enriched P2Y6 receptor to increase calcium activity during epileptogenesis. P2Y6 calcium activity is associated with lysosome biogenesis and enhanced production of NF-κB-related cytokines. In the hippocampus, knockout of the P2Y6 receptor prevents microglia from fully engulfing neurons. Attenuating microglial calcium signaling through calcium extruder (“CalEx”) expression recapitulates multiple features of P2Y6 knockout, including reduced lysosome biogenesis and phagocytic interactions. Ultimately, P2Y6 knockout mice retain more CA3 neurons and better cognitive task performance during epileptogenesis. Our results demonstrate that P2Y6 signaling impacts multiple aspects of myeloid cell immune function during epileptogenesis.",
keywords = "calcium signaling, CalEx, GRAB sensor, inflammation, microglia, P2Y6, phagocytosis, purine, seizures, UDP",
author = "Umpierre, {Anthony D.} and Bohan Li and Katayoun Ayasoufi and Simon, {Whitney L.} and Shunyi Zhao and Manling Xie and Grace Thyen and Benjamin Hur and Jiaying Zheng and Yue Liang and Bosco, {Dale B.} and Maynes, {Mark A.} and Zhaofa Wu and Xinzhu Yu and Jaeyun Sung and Johnson, {Aaron J.} and Yulong Li and Wu, {Long Jun}",
note = "We thank Dr. Bernard Robaye (Universite Libre de Bruxelles) for the P2Y6\u2212/\u2212 line and Dr. Alexander Anwar for assistance with image rendering. Institutional access to Imaris and BioRender was provided by the Mayo Foundation. This work was supported by grants from the NIH (K99 NS126417 to A.D.U.; R01 NS103212 and RF1 NS122174 to A.J.J.; and R01 NS088627 and R35 NS132326 to L.-J.W.) and the National Natural Science Foundation of China (31925017 to Y. Li). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. A.D.U. and L.-J.W. conceptualized the study and wrote the manuscript. B.L. Z.W. and Y. Li created the UDP sensor. A.D.U. S.Z. Y. Liang, and M.X. conducted in vivo experiments. K.A. conducted flow cytometry. A.D.U. and G.T. performed histology and image analysis. W.L.S. M.A.M. and D.B.B. conducted cell culture experiments. J.Z. and S.Z. performed cell isolation. B.H. and J.S. analyzed transcriptomic data. X.Y. A.J.J. Y. Li, and L.-J.W. provided reagents and equipment. Y. Li is a member of the Neuron advisory board. We thank Dr. Bernard Robaye (Universite Libre de Bruxelles) for the P2Y6 \u2212/\u2212 line and Dr. Alexander Anwar for assistance with image rendering. Institutional access to Imaris and BioRender was provided by the Mayo Foundation. This work was supported by grants from the NIH ( K99 NS126417 to A.D.U.; R01 NS103212 and RF1 NS122174 to A.J.J.; and R01 NS088627 and R35 NS132326 to L.-J.W.) and the National Natural Science Foundation of China ( 31925017 to Y. Li). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.",
year = "2024",
month = jun,
day = "19",
doi = "10.1016/j.neuron.2024.03.017",
language = "English (US)",
volume = "112",
pages = "1959--1977.e10",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "12",
}