P2Y2 receptor mediates dying cell removal via inflammatory activated microglia
Microglial removal of dying cells plays a beneficial role in maintaining homeostasis in the CNS, whereas under some pathological conditions, inflammatory microglia can cause excessive clearance, leading to neuronal death. However, the mechanisms underlying dying cell removal by inflammatory microgli...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Journal of Pharmacological Sciences |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1347861323000385 |
| _version_ | 1827890719585468416 |
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| author | Izumi Hide Hiroko Shiraki Akihiro Masuda Takuya Maeda Mayuka Kumagai Nao Kunishige Yuhki Yanase Kana Harada Shigeru Tanaka Norio Sakai |
| author_facet | Izumi Hide Hiroko Shiraki Akihiro Masuda Takuya Maeda Mayuka Kumagai Nao Kunishige Yuhki Yanase Kana Harada Shigeru Tanaka Norio Sakai |
| author_sort | Izumi Hide |
| collection | DOAJ |
| description | Microglial removal of dying cells plays a beneficial role in maintaining homeostasis in the CNS, whereas under some pathological conditions, inflammatory microglia can cause excessive clearance, leading to neuronal death. However, the mechanisms underlying dying cell removal by inflammatory microglia remain poorly understood. In this study, we performed live imaging to examine the purinergic regulation of dying cell removal by inflammatory activated microglia. Lipopolysaccharide (LPS) stimulation induces rapid death of primary rat microglia, and the surviving microglia actively remove dying cells. The nonselective P2 receptor antagonist, suramin, inhibited dying cell removal to the same degree as that of the selective P2Y2 antagonist, AR-C118925. This inhibition was more potent in LPS-stimulated microglia than in non-stimulated ones. LPS stimulation elicited distribution of the P2Y2 receptor on the leading edge of the plasma membrane and then induced drastic upregulation of P2Y2 receptor mRNA expression in microglia. LPS stimulation caused upregulation of the dying cell-sensing inflammatory Axl phagocytic receptor, which was suppressed by blocking the P2Y2 receptor and its downstream signaling effector, proline-rich tyrosine kinase (Pyk2). Together, these results indicate that inflammatory stimuli may activate the P2Y2 receptor, thereby mediating dying cell removal, at least partially, through upregulating phagocytic Axl in microglia. |
| first_indexed | 2024-03-12T21:13:41Z |
| format | Article |
| id | doaj.art-2d9172ff569342c5b292d2925a9652a7 |
| institution | Directory Open Access Journal |
| issn | 1347-8613 |
| language | English |
| last_indexed | 2024-03-12T21:13:41Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmacological Sciences |
| spelling | doaj.art-2d9172ff569342c5b292d2925a9652a72023-07-30T04:21:59ZengElsevierJournal of Pharmacological Sciences1347-86132023-09-0115315567P2Y2 receptor mediates dying cell removal via inflammatory activated microgliaIzumi Hide0Hiroko Shiraki1Akihiro Masuda2Takuya Maeda3Mayuka Kumagai4Nao Kunishige5Yuhki Yanase6Kana Harada7Shigeru Tanaka8Norio Sakai9Department of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, JapanDepartment of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, JapanDepartment of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, JapanDepartment of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; Corresponding author.Microglial removal of dying cells plays a beneficial role in maintaining homeostasis in the CNS, whereas under some pathological conditions, inflammatory microglia can cause excessive clearance, leading to neuronal death. However, the mechanisms underlying dying cell removal by inflammatory microglia remain poorly understood. In this study, we performed live imaging to examine the purinergic regulation of dying cell removal by inflammatory activated microglia. Lipopolysaccharide (LPS) stimulation induces rapid death of primary rat microglia, and the surviving microglia actively remove dying cells. The nonselective P2 receptor antagonist, suramin, inhibited dying cell removal to the same degree as that of the selective P2Y2 antagonist, AR-C118925. This inhibition was more potent in LPS-stimulated microglia than in non-stimulated ones. LPS stimulation elicited distribution of the P2Y2 receptor on the leading edge of the plasma membrane and then induced drastic upregulation of P2Y2 receptor mRNA expression in microglia. LPS stimulation caused upregulation of the dying cell-sensing inflammatory Axl phagocytic receptor, which was suppressed by blocking the P2Y2 receptor and its downstream signaling effector, proline-rich tyrosine kinase (Pyk2). Together, these results indicate that inflammatory stimuli may activate the P2Y2 receptor, thereby mediating dying cell removal, at least partially, through upregulating phagocytic Axl in microglia.http://www.sciencedirect.com/science/article/pii/S1347861323000385MicrogliaInflammationDying cell removalLipopolysaccharideP2Y2 receptor |
| spellingShingle | Izumi Hide Hiroko Shiraki Akihiro Masuda Takuya Maeda Mayuka Kumagai Nao Kunishige Yuhki Yanase Kana Harada Shigeru Tanaka Norio Sakai P2Y2 receptor mediates dying cell removal via inflammatory activated microglia Journal of Pharmacological Sciences Microglia Inflammation Dying cell removal Lipopolysaccharide P2Y2 receptor |
| title | P2Y2 receptor mediates dying cell removal via inflammatory activated microglia |
| title_full | P2Y2 receptor mediates dying cell removal via inflammatory activated microglia |
| title_fullStr | P2Y2 receptor mediates dying cell removal via inflammatory activated microglia |
| title_full_unstemmed | P2Y2 receptor mediates dying cell removal via inflammatory activated microglia |
| title_short | P2Y2 receptor mediates dying cell removal via inflammatory activated microglia |
| title_sort | p2y2 receptor mediates dying cell removal via inflammatory activated microglia |
| topic | Microglia Inflammation Dying cell removal Lipopolysaccharide P2Y2 receptor |
| url | http://www.sciencedirect.com/science/article/pii/S1347861323000385 |
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