Cited by 365Barrier Structure and Function StudiesNeuroinflammation and Neurodegeneration MechanismsTraumatic Brain Injury and Neurovascular Disturbances

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Purinergic receptor P2RY12-dependent microglial closure of the injured blood–brain barrier

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Lou, Nanhong, Takano, Takahiro, Pei, Yong, Xavier, Anna L., Goldman, Steven A., Nedergaard, Maiken·2016·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1520398113PMC PMC4743790

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Abstract

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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“…junctions and increased permeability, is a prominent pathological characteristic of both ischaemic and haemorrhagic stroke in humans.21 22 In the study by Lou et al16 discussed previously, the vascular injury mouse model was associated with extravascular leakage, suggesting compromise of the BBB.”
Background
Long-term microglial phase-specific dynamics during single vessel occlusion and recanalization
Xie, X., Liu, X., Zhu, J., Xu, Y., Li, X., Zheng, Y., Gong, S., Xiao, X., Chen, Y., Zhang, J., et al. (2022) · Communications Biology · doi:10.1038/s42003-022-03784-0 · Cited by 5
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“[24] This could also play a role in the association of APT with the occurrence of RCMA that we observed, but in the end the exact underlying mechanisms still remain unclear.”
Background
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“Microglia has neuroprotective effects in the acute phase of stroke, 68 and microglia processes are necessary for the closure of the BBB. 69 Our observation indicates that altered recruiting of microglia is associated to greater damage, suggesting that prevention of inflammation spread is impaired.”
Background
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“P2RY12 is of particular interest because its expression has been linked to microglial closure of the blood-brain barrier (BBB) at sites of injury (Lou et al., 2016) and is required for the attachment of microglia to capillary walls (Bisht et al., 2021).”
Protein Networks in Alzheimer’s Disease
Carlsen, E. M., & Rasmussen, R. N. (2017) · Cell Systems · doi:10.1016/j.cels.2017.02.006 · Cited by 3
“…of brain homeostasis and reliable neuronal signaling with responsibilities suchasneurotransmitter clearance, extracellular ion buffering, protective reactions to cellular insults and for axonal action potential conductance (Baumann and Pham-Dinh, 2001; Khakh and Sofroniew, 2015; Lou et al., 2016).”
Background
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“Emerging work has implicated microglia in regulating blood flow and closure of injured vascular barriers (16,18,64).”
Background
Intracortical microstimulation induces rapid microglia process convergence
Williams, N. P., Kelly, A. M., Zheng, X. S., Vazquez, A. L., & Cui, X. T. (2025) · Biomaterials · doi:10.1016/j.biomaterials.2025.123732 · Cited by 2
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“Lou et al. [11] demonstrated that microglia can quickly converge on and seal damaged areas of the BBB via P2Y12 receptors within minutes.”
Influential
Microglia sense fungal infections through capsular components from capillary-bound Cryptococcus neoformans via endothelial nucleotide signaling
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“Our study aligns with previous models showing P2Y12 signaling is required for microglial response [5,37,38,47].”
Influential
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Bi, Q., Guo, C., Chen, N., Zhou, X., Zhou, Q., Liu, X., Shen, X. Z., & Shi, P. D. (2026) · Physiology · doi:10.1152/physiol.00030.2025 · Cited by 3
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Gauthey, W., Lin, A., Ahmed, O. M., Leifer, A. M., Murthy, M., & Thiberge, S. Y. (2026) · Nature Communications · doi:10.1038/s41467-026-72437-1 · Cited by 6
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Gong, M., Li, X., Yuan, Q., Lina, P. A. N. G., Ye, X., Li, S., Li, Y., Guo, H., & Jin, S. (2026) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2026.1821227 · Cited by 2
“The Purinergic receptor P2Y, G-protein coupled, 12 (P2RY12), a marker associated with homeostatic microglia, plays a critical role in the rapid repair of the BBB following injury (Lou et al., 2016).”
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Aertker, B. M., Kumar, A., Cardenas, F., Gudenkauf, F. J., Sequeira, D. J., Prossin, A. R., Srivastava, A. K., Cox, C. S., & Bedi, S. S. (2021) · ASN NEURO · doi:10.1177/17590914211014135 · Cited by 2
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Zhang, F., Wu, L.-B., Yu, Q., Wang, M., Zeng, X.-L., Wei, X., Wu, Z., Cai, R.-L., & Hu, L. (2021) · Neurochemical Journal · doi:10.1134/s1819712421040176 · Cited by 2
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Influential
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“32,44 PKA substrate phosphorylation (using anti p -PKA substrate antibody) was used as an indirect readout of cAMP levels.”
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“This form of ‘microglial process motility’ is crucial for the clearance of cellular debris, interaction with neurons and other glial components, and to remodel the extracellular matrix [17, 18].”
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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)
ORCID: Takano, Takahiro
Xavier, Anna L.
Goldman, Steven A.
Nedergaard, Maiken
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
DOI: 10.1073/pnas.1520398113
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
Licence: www.pnas.org/preview_site/misc/userlicense.xhtml (vor, 182 d)
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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Purinergic receptor P2RY12-dependent microglial closure of the injured blood–brain barrier

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