Thomas Deluc, Ariel Ase, Marie-France Dorion, Gilles Maussion, Yeman Tang, Rita T M Lo, Irina Shlaifer, Valerio E Piscopo, Thomas M Durcan, Stefano Stifani, Philippe Séguéla
{"title":"鼠和人小胶质细胞中P2Y6受体依赖性吞噬的肾上腺素能调控。","authors":"Thomas Deluc, Ariel Ase, Marie-France Dorion, Gilles Maussion, Yeman Tang, Rita T M Lo, Irina Shlaifer, Valerio E Piscopo, Thomas M Durcan, Stefano Stifani, Philippe Séguéla","doi":"10.1002/glia.70054","DOIUrl":null,"url":null,"abstract":"<p><p>Microglia, the resident immune cells of the central nervous system (CNS), are in constant survey of their environment. Extracellular nucleotides, released by stressed and damaged neurons, act as danger signals to microglia through various purinergic/pyrimidinergic receptors. In the CNS, the UDP receptor P2Y6 is mostly expressed in microglia, where its activation induces phagocytosis, a homeostatic function that is dysregulated in several neurodegenerative diseases and in chronic pain. Yet, modulatory mechanisms impacting P2Y6 activity remain to be identified. The microglial β2 adrenergic receptor (ADRB2) for norepinephrine represents a promising candidate for modulation of P2Y6 receptors. Our calcium imaging data indicate that exposure to the ADRB2 agonist isoproterenol inhibits the calcium transients evoked by activation of Gq-coupled P2Y6 receptors in primary mouse microglia. This functional modulation, suppressed by the selective ADRB2 antagonist ICI-118551, is conserved in human iPSC-derived microglia. Accordingly, we observed that the phagocytotic activity induced by P2Y6 is reduced by ADRB2 signaling in both mouse and human microglia. Finally, we report that ADRB2 activation is linked to a decrease in P2Y6 mRNA expression. These findings provide evidence that metabotropic and transcriptional crosstalks between nucleotide and adrenergic transductions control microglial responses in the CNS, potentially contributing to the pathophysiology of neuro-immune disorders and chronic pain conditions.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":" ","pages":"2025-2034"},"PeriodicalIF":5.1000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334858/pdf/","citationCount":"0","resultStr":"{\"title\":\"Adrenergic Control of P2Y6 Receptor-Dependent Phagocytosis in Rodent and Human Microglia.\",\"authors\":\"Thomas Deluc, Ariel Ase, Marie-France Dorion, Gilles Maussion, Yeman Tang, Rita T M Lo, Irina Shlaifer, Valerio E Piscopo, Thomas M Durcan, Stefano Stifani, Philippe Séguéla\",\"doi\":\"10.1002/glia.70054\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Microglia, the resident immune cells of the central nervous system (CNS), are in constant survey of their environment. Extracellular nucleotides, released by stressed and damaged neurons, act as danger signals to microglia through various purinergic/pyrimidinergic receptors. In the CNS, the UDP receptor P2Y6 is mostly expressed in microglia, where its activation induces phagocytosis, a homeostatic function that is dysregulated in several neurodegenerative diseases and in chronic pain. Yet, modulatory mechanisms impacting P2Y6 activity remain to be identified. The microglial β2 adrenergic receptor (ADRB2) for norepinephrine represents a promising candidate for modulation of P2Y6 receptors. Our calcium imaging data indicate that exposure to the ADRB2 agonist isoproterenol inhibits the calcium transients evoked by activation of Gq-coupled P2Y6 receptors in primary mouse microglia. This functional modulation, suppressed by the selective ADRB2 antagonist ICI-118551, is conserved in human iPSC-derived microglia. Accordingly, we observed that the phagocytotic activity induced by P2Y6 is reduced by ADRB2 signaling in both mouse and human microglia. Finally, we report that ADRB2 activation is linked to a decrease in P2Y6 mRNA expression. These findings provide evidence that metabotropic and transcriptional crosstalks between nucleotide and adrenergic transductions control microglial responses in the CNS, potentially contributing to the pathophysiology of neuro-immune disorders and chronic pain conditions.</p>\",\"PeriodicalId\":174,\"journal\":{\"name\":\"Glia\",\"volume\":\" \",\"pages\":\"2025-2034\"},\"PeriodicalIF\":5.1000,\"publicationDate\":\"2025-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334858/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Glia\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/glia.70054\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/7/15 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Glia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/glia.70054","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/7/15 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Adrenergic Control of P2Y6 Receptor-Dependent Phagocytosis in Rodent and Human Microglia.
Microglia, the resident immune cells of the central nervous system (CNS), are in constant survey of their environment. Extracellular nucleotides, released by stressed and damaged neurons, act as danger signals to microglia through various purinergic/pyrimidinergic receptors. In the CNS, the UDP receptor P2Y6 is mostly expressed in microglia, where its activation induces phagocytosis, a homeostatic function that is dysregulated in several neurodegenerative diseases and in chronic pain. Yet, modulatory mechanisms impacting P2Y6 activity remain to be identified. The microglial β2 adrenergic receptor (ADRB2) for norepinephrine represents a promising candidate for modulation of P2Y6 receptors. Our calcium imaging data indicate that exposure to the ADRB2 agonist isoproterenol inhibits the calcium transients evoked by activation of Gq-coupled P2Y6 receptors in primary mouse microglia. This functional modulation, suppressed by the selective ADRB2 antagonist ICI-118551, is conserved in human iPSC-derived microglia. Accordingly, we observed that the phagocytotic activity induced by P2Y6 is reduced by ADRB2 signaling in both mouse and human microglia. Finally, we report that ADRB2 activation is linked to a decrease in P2Y6 mRNA expression. These findings provide evidence that metabotropic and transcriptional crosstalks between nucleotide and adrenergic transductions control microglial responses in the CNS, potentially contributing to the pathophysiology of neuro-immune disorders and chronic pain conditions.
期刊介绍:
GLIA is a peer-reviewed journal, which publishes articles dealing with all aspects of glial structure and function. This includes all aspects of glial cell biology in health and disease.