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Purinergic receptor P2RY12-dependent microglial closure of the injured blood–brain barrier
Open accessAbstract
Significance: Brain endothelial cells, pericytes, and astrocytes participate in maintenance of the blood–brain barrier (BBB). Juxtavascular microglial cells are also an integral part of the neurovascular unit. We show here that, in response to capillary injury, microglial processes rapidly form a dense plexiform aggregate at the site of injury. Photoablation of microglial cells abolished closure of BBB leakage, whereas inhibition of P2RY12 (purinergic receptor P2Y, G-protein coupled, 12) receptors suppressed microglial process motility and prolonged BBB closure. Thus, microglial cells mediate rapid resealing of injury-induced leaks in BBB. These observations may have clinical importance as P2RY12 receptor antagonists are widely used as platelet inhibitors in patients with coronary artery and cerebrovascular disease at risk for stroke and its attendant disruption of the injured BBB.
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“Although initially considered 'quiescent' cells primarily responsible for clearing cellular debris in the brain, microglia are now known as dynamic players in synaptic pruning, maintaining homeostasis and are primary responders to insult and injury in the CNS (Lou et al, 2016;Nimmerjahn et al, 2005;Paolicelli et al, 2011).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Lou et al, 2016
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“In this model, focal cerebrovascular damage resulted in a rapid, purinergic receptor–dependent projection of microglia processes that walled off the damaged vessel, limiting the extent of BBB leakage (134).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [134]
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“These appear to help clear debris and restore disrupted astrocytic glial limitans and BBB integrity.(64) When this response is blocked in experimental injury models, parenchymal destruction is more profound.”
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“The microglial survey mediates the immune response, supports the homeostasis of the neurons and, in collaboration with astrocytes, maintains the integrity of the blood-brain barrier (BBB) [23, 32, 37].”
A “multi-omics” analysis of blood–brain barrier and synaptic dysfunction in APOE4 mice
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“These findings were consistent with data showing that microglia migrate rapidly to the sites of capillary wall lesions to seal and repair damaged BBB, which requires G protein – coupled purinergic receptor P2RY12 (Haruwaka et al., 2019; Lou et al., 2016).”
Microvascular anomaly conditions in psychiatric disease. Schizophrenia – angiogenesis connection
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“Moreover, the critical contribution of microglia to the repair of damaged BBB, which involves mechanisms elicited by purinergic receptor signaling, has been demonstrated recently (Lou et al., 2016).”
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“By contrast, recent experimental studies revealed that juxtavascular microglial cells are critical in mediating rapid closure/repair of small leaks in the BBB (19) .”
ResultWhat are activated and reactive glia and what is their role in neurodegeneration?
Bennett, M. L., & Viaene, A. N. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105172 · Cited by 77
Mice deficient in NRROS show abnormal microglial development and neurological disorders
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Microglial Displacement of GABAergic Synapses Is a Protective Event during Complex Febrile Seizures
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Wide-field fluorescence lifetime imaging of neuron spiking and subthreshold activity in vivo
Bowman, A. J., Huang, C., Schnitzer, M. J., & Kasevich, M. A. (2023) · Science · doi:10.1126/science.adf9725 · Cited by 73
Gliotransmitters and cytokines in the control of blood-brain barrier permeability
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Microglia Receptors in Animal Models of Traumatic Brain Injury
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Imaging extracellular ATP with a genetically-encoded, ratiometric fluorescent sensor
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How the immune system shapes neurodegenerative diseases
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Affective Immunology: The Crosstalk Between Microglia and Astrocytes Plays Key Role?
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“Besides, resting microglia is beneficial for relatively intact BBB, while reactive microglia tend tomigrate and induce BBB breakdown (138).”
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“…to cortical injury ( Haynes et al., 2006 ; Cserép et al., 2020 ), NLRP3 inflammasome activation ( Suzuki et al., 2020 ; Wu et al., 2019 ), neuronal hyperactivity and protection ( Cserép et al., 2020 ; Eyo et al., 2014 ), and blood-brain barrier maintenance ( Lou et al., 2016 ; Bisht et al., 2021 ).”
Metabolic Syndrome and the Cellular Phase of Alzheimer's Disease
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Potential microglia‐based interventions for stroke
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Heritability Enrichment Implicates Microglia in Parkinson's Disease Pathogenesis
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“thrombotic compound clopidogrel, which has been shown experimentally to inhibit microglial P2RY12 in the context of blood-brain barrier breakdown.(43) Further studies are clearly needed, but given that fact that this molecule is an established drug-target, we anticipate potentially important clinical implications if m…”
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Microglia as the Critical Regulators of Neuroprotection and Functional Recovery in Cerebral Ischemia
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Microglial Responses to Brain Injury and Disease: Functional Diversity and New Opportunities
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Pannexin-1 Channels as Mediators of Neuroinflammation
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“, ATP or UDP), and the activation of P2Y6, P2Y12, and P2X4 receptors [37,38].”
BackgroundMacrophage compartmentalization in the brain and cerebrospinal fluid system
Munro, D. A. D., Movahedi, K., & Priller, J. (2022) · Science Immunology · doi:10.1126/sciimmunol.abk0391 · Cited by 59
Remodeling of the Neurovascular Unit Following Cerebral Ischemia and Hemorrhage
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Targeting NLRP3 Inflammasome in Translational Treatment of Nervous System Diseases: An Update
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“Inhibiting this response of microglia can significantly increase the permeability of capillaries (Lou et al., 2016).”
BackgroundRegion-Specific Phenotypes of Microglia: The Role of Local Regulatory Cues
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The impact of genetic manipulation of laminin and integrins at the blood–brain barrier
Halder, S. K., Sapkota, A., & Milner, R. (2022) · Fluids and Barriers of the CNS · doi:10.1186/s12987-022-00346-8 · Cited by 58
Schneider, R., Leven, P., Mallesh, S., Breßer, M., Schneider, L. H., Mazzotta, E. A., Fadda, P., Glowka, T. R., Vilz, T. O., Lingohr, P., et al. (2022) · Communications Biology · doi:10.1038/s42003-022-03772-4 · Cited by 56
The G protein-coupled receptor GPR34 – The past 20 years of a grownup
Schöneberg, T., Meister, J., Knierim, A. B., & Schulz, A. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.04.008 · Cited by 54
Profaci, C. P., Harvey, S. S., Bajc, K., Zhang, T. Z., Jeffrey, D. A., Zhang, A. Z., Nemec, K. M., Davtyan, H., O’Brien, C. A., McKinsey, G. L., et al. (2024) · Neuron · doi:10.1016/j.neuron.2024.07.015 · Cited by 58
Concerted pulsatile and graded neural dynamics enables efficient chemotaxis in C. elegans
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“For example, microglia processes have been shown to reseal injured capillaries following recruitment via P2ry12 mediated chemotaxis [65].”
BackgroundMicroglia and Microglia-Like Cells: Similar but Different
Cuadros, M. Á., Sepúlveda, M. R., Martín‐Oliva, D., Marín‐Teva, J. L., & Neubrand, V. E. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.816439 · Cited by 57
“In addition, microglia depletion can directly affect the integrity of the BBB, as microglia contribute to the closure of small openings in the BBB produced during the normal replacement of endothelial cells or in pathological situations (Lou et al., 2016; Taylor et al., 2018).”
Background
Metadata
- Authors
- Lou, N., Takano, T., Pei, Y., Xavier, A. L., Goldman, S. A., & Nedergaard, M.
- Affiliations
- University of Rochester Medicine (US)
- University of Copenhagen (DK)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-01-11
- Volume
- 113
- Issue
- 4
- Pages
- 1074-1079
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4743790
- OpenAlex
- W2234493563
- Cited by
- 364
- References
- 56
- Citations by year
- 2026: 31 · 2025: 31 · 2024: 50 · 2023: 53 · 2022: 59 · 2021: 26 · 2020: 40 · 2019: 24 · 2018: 23 · 2017: 20 · 2016: 6
- FWCI
- 13.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- Funders
- NIH/NIDCR (R01DE022743)
- NIH/NINDS (R01NS075177)
- NIH/NCCIH (R01AT007945)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- P2Y12 receptor, microglia, blood-brain barrier integrity, microglial chemotaxis, neurovascular unit, cerebrovascular injury, clopidogrel, G protein-coupled receptors
- MeSH terms
- Clopidogrel, Animals, Blood-Brain Barrier, Cell Movement, Male, Mice, Inbred C57BL, Platelet Aggregation Inhibitors, Ticlopidine, Microglia, Mice, Receptors, Purinergic P2Y12
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