The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury
Open accessAbstract
The migration of polymorphonuclear granulocytes (PMN) into the brain parenchyma and release of their abundant proteases are considered the main causes of neuronal cell death and reperfusion injury following ischemia. Yet, therapies targeting PMN egress have been largely ineffective. To address this discrepancy we investigated the temporo-spatial localization of PMNs early after transient ischemia in a murine transient middle cerebral artery occlusion (tMCAO) model and human stroke specimens. Using specific markers that distinguish PMN (Ly6G) from monocytes/macrophages (Ly6C) and that define the cellular and basement membrane boundaries of the neurovascular unit (NVU), histology and confocal microscopy revealed that virtually no PMNs entered the infarcted CNS parenchyma. Regardless of tMCAO duration, PMNs were mainly restricted to luminal surfaces or perivascular spaces of cerebral vessels. Vascular PMN accumulation showed no spatial correlation with increased vessel permeability, enhanced expression of endothelial cell adhesion molecules, platelet aggregation or release of neutrophil extracellular traps. Live cell imaging studies confirmed that oxygen and glucose deprivation followed by reoxygenation fail to induce PMN migration across a brain endothelial monolayer under flow conditions in vitro. The absence of PMN infiltration in infarcted brain tissues was corroborated in 25 human stroke specimens collected at early time points after infarction. Our observations identify the NVU rather than the brain parenchyma as the site of PMN action after CNS ischemia and suggest reappraisal of targets for therapies to reduce reperfusion injury after stroke.
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These neutrophils become confined by the astrocytic basement membrane and glia limitans to the perivascular space.
“However, these cells become confined by the astrocytic basement membrane and glia limitans to the perivascular space (143, 144).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [143]
Neuroinflammation is a key component of cell death cascades in stroke, with microglial cells and peripheral leukocytes, especially neutrophils and monocytes/macrophages, as main players.
“One of the key components of the cell death cascades in stroke is neuroinflammation, where the main players are microglial cells and the peripheral leukocytes, especially neutrophils and monocytes/macrophages.”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Enzmann et al., 2013
After ischemic insult, recruitment of immune cells occurs in a biphasic dynamics: in the acute phase (within minutes), microglial cells are rapidly recruited to the injury site due to immediate release of cytokines and chemokines.
“After the ischemic insult, the recruitment of immune cells occurs in a biphasic dynamics. In the acute phase (within minutes), microglial cells are rapidly recruited to the injury site, due to the immediate release of cytokines and chemokines.”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Enzmann et al., 2013
In the acute phase, activated microglia enhance release of ROS (through NADPH oxidase and MPO), cytokines (IL-1β, IL-6, TNF-α) and chemokines (MCP-1, CXCL-1, MIP-1α).
“These cells are activated, enhancing the release of ROS (through NADPH oxidase and MPO), cytokines (i.e., IL-1β, IL-6 and TNF-α) and chemokines (MCP-1, CXCL-1 and MIP-1α).”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Enzmann et al., 2013
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(2004) · Springer eBooks · doi:10.1007/978-3-662-05426-0 · Cited by 10 · see citing works
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Research works printed but not linked: 1
- [40]Glaser JS Neuro-ophthalmology 1999 Philadelphia Lippincott Williams & Wilkins
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Development, maintenance and disruption of the blood-brain barrier
Obermeier, B., Daneman, R., & Ransohoff, R. M. (2013) · Nature Medicine · doi:10.1038/nm.3407 · Cited by 2,452 · see citing works
Immune responses to stroke: mechanisms, modulation, and therapeutic potential.
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The impact of microglial activation on blood-brain barrier in brain diseases
da Fonseca, A. C. C., Matias, D., Garcia, C., Amaral, R., Geraldo, L. H., Freitas, C., & Lima, F. R. S. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00362 · Cited by 572 · see citing works
Neutrophil recruitment to the brain in mouse and human ischemic stroke
Perez-de-Puig, I., Miró-Mur, F., Ferrer-Ferrer, M., Gelpi, E., Pedragosa, J., Justicia, C., Urra, X., Chamorro, A., & Planas, A. M. (2015) · Acta Neuropathologica · doi:10.1007/s00401-014-1381-0 · Cited by 420 · see citing works
The anatomy and immunology of vasculature in the central nervous system
Mastorakos, P., & McGavern, D. (2019) · Science Immunology · doi:10.1126/sciimmunol.aav0492 · Cited by 333 · see citing works
Advances in Meningeal Immunity
Rua, R., & McGavern, D. B. (2018) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.04.003 · Cited by 326 · see citing works
Marchetti, L., & Engelhardt, B. (2020) · Vascular Biology · doi:10.1530/vb-19-0033 · Cited by 304 · see citing works
Microglial cell loss after ischemic stroke favors brain neutrophil accumulation
Otxoa-de-Amezaga, A., Miró-Mur, F., Pedragosa, J., Gallizioli, M., Justicia, C., Gaja-Capdevila, N., Ruíz-Jaen, F., Salas-Perdomo, A., Bosch, A., Calvo, M., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-018-1954-4 · Cited by 258 · see citing works
Lopes Pinheiro, M. A., Kooij, G., Mizee, M. R., Kamermans, A., Enzmann, G., Lyck, R., Schwaninger, M., Engelhardt, B., & de Vries, H. E. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.10.018 · Cited by 247 · see citing works
Self-citationColes, J. A., Myburgh, E., Brewer, J. M., & McMenamin, P. G. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.05.002 · Cited by 123 · see citing works
Brain-to-cervical lymph node signaling after stroke.
Esposito, E., Ahn, B. J., Shi, J., Nakamura, Y., Park, J. H., Mandeville, E. T., Yu, Z., Chan, S. J., Desai, R., Hayakawa, A., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-13324-w · Cited by 123 · see citing works
Enzmann, G., Kargaran, S., & Engelhardt, B. (2018) · Therapeutic Advances in Neurological Disorders · doi:10.1177/1756286418794184 · Cited by 119 · see citing works
Self-citation
- Authors
- Enzmann, G., Mysiorek, C., Gorina, R., Cheng, Y.-J., Ghavampour, S., Hannocks, M.-J., Prinz, V., Dirnagl, U., Endres, M., Prinz, M., Beschorner, R., Harter, P. N., Mittelbronn, M., Engelhardt, B., & Sorokin, L.
- Affiliations
- University of Bern (CH)
- University of Münster (DE)
- Center for Stroke Research Berlin (DE)
- University of Freiburg (DE)
- University of Tübingen (DE)
- Goethe University Frankfurt (DE)
- Corresponding author
- Mittelbronn, Michel
- Engelhardt, Britta
- Sorokin, Lydia
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2012-12-27
- Volume
- 125
- Issue
- 3
- Pages
- 395-412
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC3578720
- OpenAlex
- W2020283277
- Cited by
- 225
- References
- 91
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 13 · 2023: 14 · 2022: 17 · 2021: 23 · 2020: 14 · 2019: 15 · 2018: 24 · 2017: 14 · 2016: 16 · 2015: 20 · 2014: 21 · 2013: 17
- FWCI
- 9.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- reroDoc Digital Library (submittedVersion)
- HAL (submittedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, other-oa)
- Open Access CRIS of the University of Bern
- Funders
- University of Bern
- European Commission (2007–2013, FP7 2007-2013, FP7/2007, 202213, 201024)
- Deutsche Forschungsgemeinschaft (FP7/2007–2013, TR 43, SFBTR43)
- Bundesministerium für Bildung und Forschung
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- neurovascular unit, polymorphonuclear leukocytes, neutrophil infiltration, cerebral ischemia, stroke, transient middle cerebral artery occlusion, ischemia-reperfusion injury, Ly6G, Ly6C, perivascular spaces, neutrophil extracellular traps, oxygen-glucose deprivation, brain endothelium, stroke therapy targets
- MeSH terms
- Animals, Hypoxia, Antigens, Ly, Blood Vessels, Blood-Brain Barrier, Brain, Cells, Cultured, Disease Models, Animal, Endothelium, Gene Expression Regulation, Glucose, Granulocytes, Humans, Functional Laterality, Male, Mice, Inbred C57BL, Models, Biological, Oxygen, Antigens, CD, Cell Adhesion Molecules, Infarction, Middle Cerebral Artery, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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