Microglial P2Y6 calcium signaling promotes phagocytosis and shapes neuroimmune responses in epileptogenesis
Copyright © 2024 Elsevier Inc. All rights reserved..
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.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Neuron - (2024) vom: 10. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Umpierre, Anthony D [VerfasserIn] |
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CalEx |
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Date Revised 22.04.2024 published: Print-Electronic UpdateOf: bioRxiv. 2023 Jun 13;:. - PMID 37398001 Citation Status Publisher |
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| doi: |
10.1016/j.neuron.2024.03.017 |
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| PPN (Katalog-ID): |
NLM371034132 |
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| 520 | |a 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 | ||
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| 700 | 1 | |a Simon, Whitney L |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Shunyi |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Manling |e verfasserin |4 aut | |
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| 700 | 1 | |a Hur, Benjamin |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Jiaying |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Yue |e verfasserin |4 aut | |
| 700 | 1 | |a Bosco, Dale B |e verfasserin |4 aut | |
| 700 | 1 | |a Maynes, Mark A |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Zhaofa |e verfasserin |4 aut | |
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