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The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS.
Open accessAbstract
Meninges that surround the CNS consist of an outer fibrous sheet of dura mater (pachymeninx) that is also the inner periosteum of the skull. Underlying the dura are the arachnoid and pia mater (leptomeninges) that form the boundaries of the subarachnoid space. In this review we (1) examine the development of leptomeninges and their role as barriers and facilitators in the foetal CNS. There are two separate CSF systems during early foetal life, inner CSF in the ventricles and outer CSF in the subarachnoid space. As the foramina of Magendi and Luschka develop, one continuous CSF system evolves. Due to the lack of arachnoid granulations during foetal life, it is most likely that CSF is eliminated by lymphatic drainage pathways passing through the cribriform plate and nasal submucosa. (2) We then review the fine structure of the adult human and rodent leptomeninges to establish their roles as barriers and facilitators for the movement of fluid, cells and pathogens. Leptomeningeal cells line CSF spaces, including arachnoid granulations and lymphatic drainage pathways, and separate elements of extracellular matrix from the CSF. The leptomeningeal lining facilitates the traffic of inflammatory cells within CSF but also allows attachment of bacteria such as Neisseria meningitidis and of tumour cells as CSF metastases. Single layers of leptomeningeal cells extend into the brain closely associated with the walls of arteries so that there are no perivascular spaces around arteries in the cerebral cortex. Perivascular spaces surrounding arteries in the white matter and basal ganglia relate to their two encompassing layers of leptomeninges. (3) Finally we examine the roles of ligands expressed by leptomeningeal cells for the attachment of inflammatory cells, bacteria and tumour cells as understanding these roles may aid the design of therapeutic strategies to manage developmental, autoimmune, infectious and neoplastic diseases relating to the CSF, the leptomeninges and the associated CNS.
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“Single-cell profiling suggested functions shared with microglia and astrocytes in maintaining CNS homeostasis [372] and regulating barrier functions [367,378,379,380].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [380]
Experimental — accuracy not yet measuredIn the citing paper
“All major meningitis causing bacteria can adhere strongly to meningeal fibroblasts and arachnoid barrier-like cells”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Weller et al., 2018
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“CSF provides physical cushioning while delivering nutrients and remov ing waste for CNS tissues ( 12 ).”
Herold, R., Schroten, H., & Schwerk, C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20215393 · Cited by 48
“Another major barrier protecting the brain is the BCSFB, which can be separated into a barrier to the inner CSF in the ventricles at the choroid plexus (CP) and barriers to the outer CSF located at the arachnoidea and blood vessels present in the subarachnoidal space [15].”
BackgroundRahman, M. M., Lee, J., Kim, Y. H., & Park, C. (2023) · Biomedicines · doi:10.3390/biomedicines11051413 · Cited by 43
“Similarly, as compared to humans, rodents have a lower relative amount of CSF and slower rates of CSF circulation, but they have similar systems for production and circulation [1,31,33,81].”
BackgroundThe blood–CSF–brain route of neurological disease: The indirect pathway into the brain
Cousins, O., Hodges, A., Schubert, J. J., Veronese, M., Turkheimer, F., Miyan, J. A., Engelhardt, B., & Roncaroli, F. (2021) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12789 · Cited by 49
“Human postmortem studies have questioned the existence of VRS at the brain cortex suggesting that VRS are restricted to the basal ganglia and white matter [33].”
BackgroundHayden, M. R., & Banks, W. A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115427 · Cited by 41
Diem, A. K., Carare, R. O., Weller, R. O., & Bressloff, N. W. (2018) · PLoS ONE · doi:10.1371/journal.pone.0205276 · Cited by 41
Ma, T., Wang, F., Xu, S., & Huang, J. H. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.01.028 · Cited by 38
Subpial Hemorrhage in Neonates: What Radiologists Need to Know
Barreto, A. R. F., Carrasco, M., Dabrowski, A. K., Sun, L. R., & Tekes, A. (2021) · American Journal of Roentgenology · doi:10.2214/ajr.20.22999 · Cited by 40
The lymphatic system: a therapeutic target for central nervous system disorders
Lü, H., Cao, Y., Hu, J., Xu, J., Liu, Q., Huang, S., & Duan, C. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.355741 · Cited by 43
“In the traditional routes, the molecular contents of the CSF are cleared via arachnoid granulations into the dural venous sinus, through the cribriform plate into the nasal mucosa, and via transporters and receptors present on the apical side of the choroid plexus epithelium (Weller et al., 2018).”
BackgroundA mosquito mouthpart-like bionic neural probe
Zhou, Y., Yang, H., Wang, X., Yang, H., Sun, K., Zhou, Z., Sun, L., Zhao, J., Tao, T. H., & Wei, X. (2023) · Microsystems & Nanoengineering · doi:10.1038/s41378-023-00565-5 · Cited by 37
The anatomic basis of leptomeningeal metastasis
Freret, M. E., & Boire, A. A. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20212121 · Cited by 42
“The meninges that surround the brain and spinal cord comprise three layers (reviewed in Weller et al., 2018).”
BackgroundBreaching Brain Barriers: B Cell Migration in Multiple Sclerosis
Rodriguez-Mogeda, C., Rodríguez‐Lorenzo, S., Attia, J. V. D., van Horssen, J., Witte, M. E., & de Vries, H. E. (2022) · Biomolecules · doi:10.3390/biom12060800 · Cited by 36
“Directly attached to the meningeal dural mater layer is the arachnoid mater, a translucent multilayer of dense leptomeningeal cells [62].”
BackgroundInfluentialCentral Nervous System Fibroblast-Like Cells in Stroke and Other Neurological Disorders
Xu, L., & Yao, Y. (2021) · Stroke · doi:10.1161/strokeaha.120.033431 · Cited by 34
Use of supercritical CO2 in soft tissue decellularization
Topuz, B., Günal, G., Guler, S., & Aydın, H. M. (2019) · Methods in cell biology · doi:10.1016/bs.mcb.2019.10.012 · Cited by 34
VEGFR2 signaling drives meningeal vascular regeneration upon head injury
Koh, B. I., Lee, H. J., Kwak, P. A., Yang, M. J., Kim, J., Kim, H.-S., Koh, G. Y., & Kim, I. (2020) · Nature Communications · doi:10.1038/s41467-020-17545-2 · Cited by 30
Spekker, O., Schultz, M., Paja, L., Váradi, O. A., Molnár, E., Pálfi, G., & Hunt, D. R. (2020) · PLoS ONE · doi:10.1371/journal.pone.0238444 · Cited by 32
Dankner, M., Lam, S., Degenhard, T., Garzia, L., Guiot, M., Petrecca, K., & Siegel, P. M. (2021) · Cancers · doi:10.3390/cancers13040732 · Cited by 32
“The brain and spinal cord are surrounded by tissues called meninges (Figure 1) [26].”
BackgroundInfluentialAssis, Z., Kirton, A., Pauranik, A., Sherriff, M., & Wei, X. (2020) · American Journal of Neuroradiology · doi:10.3174/ajnr.a6872 · Cited by 30
“However, the veins coursing through the subpial space may or may not be invested by the pia mater.(12) Hence, it could be speculated that cortical veins, unlike cortical arteries, which have little-or-no leptomeningeal investment around them, can bleed directly into the subpial space.”
BackgroundInternal State: Dynamic, Interconnected Communication Loops Distributed Across Body, Brain, and Time
Kanwal, J. K., Coddington, E. J., Frazer, R., Limbania, D., Turner, G., Davila, K. J., Givens, M. A., Williams, V. M., Datta, S. R., & Wasserman, S. M. (2021) · Integrative and Comparative Biology · doi:10.1093/icb/icab101 · Cited by 30
“These structures at the interface include but are not limited to the lymphatic system, glymphatic system, meninges, blood vasculature, choroid plexus, glial cells, and the skin (Paus et al. 2006; Chen and Lyga 2014; Jessen et al. 2015; Weller et al. 2018; Wilton et al. 2019; Decimo et al. 2020; Kaplan et al. 2020; Tho…”
BackgroundSoden, P. A., Henderson, A. R., & Lee, E. (2022) · Advanced Biology · doi:10.1002/adbi.202200027 · Cited by 35
Chae, J., Choi, M., Choi, J., & Yoo, S. (2024) · Animal Cells and Systems · doi:10.1080/19768354.2024.2307559 · Cited by 31
“Cerebrospinal fl uid (CSF) is a fl uid that fl ows within the central nervous system (CNS), and most is found in the cranial or spinal subarachnoid space (SAS).”
BackgroundInfluentialDevelopment of a Multicomponent Intervention to Prevent Alzheimer's Disease
Saitô, S., Yamamoto, Y., & Ihara, M. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00490 · Cited by 30
“Interestingly, IPAD was impaired in the aging mouse brain and in the presence of CAA (106).”
BackgroundInfluentialTargeting the Choroid Plexuses for Protein Drug Delivery
Bryniarski, M. A., Ren, T., Rizvi, A. R., Snyder, A. M., & Morris, M. E. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12100963 · Cited by 28
Bacterial meningitis in the early postnatal mouse studied at single-cell resolution
Wang, J., Rattner, A., & Nathans, J. (2023) · eLife · doi:10.7554/elife.86130 · Cited by 24
“The brain and spinal cord are protected, both physically and immunologically, by the meninges, a multi-layered tissue that occupies the space between the CNS parenchyma and the surrounding bone (Figure 1A; Coles et al., 2017a ; Weller et al., 2018 ).”
BackgroundWidespread distribution of lymphatic vessels in human dura mater remote from sinus veins
Quesada, C. L. V., Rao, S. B., Torp, R., & Eide, P. K. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1228344 · Cited by 26
“These MLVs were found to carry substances and waste from the cerebrospinal fl uid (CSF), and impairing their function reduced ef fl ux of toxic waste substances from CSF (Zou et al., 2019; Da Mesquita et al., 2021; Ding et al., 2021).”
InfluentialBrain Barriers and Multiple Sclerosis: Novel Treatment Approaches from a Brain Barriers Perspective
Nishihara, H., & Engelhardt, B. (2020) · Handbook of experimental pharmacology · doi:10.1007/164_2020_407 · Cited by 27
Hayden, M. R., Grant, D. G., Aroor, A. R., & DeMarco, V. G. (2018) · Neuroglia · doi:10.3390/neuroglia1010015 · Cited by 23
“Concurrent with the above findings, other groups identified lymphatic channels in the meninges, and suggested that the drainage was accomplished via a “perivascular channel” that moves within the basal lamina regions of the outer arteriole smooth muscle cells and adventitia [54].”
ResultThe contribution of the meningeal immune interface to neuroinflammation in traumatic brain injury
Mokbel, A. Y., Burns, M. P., & Main, B. S. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03122-7 · Cited by 25
“In addition, the dura contains fenestrated blood vessels and lymphatics that form a connection with the periphery [171–176].”
BackgroundPlog, B. A., Kim, K., Verhaege, D., Kim, M. W., Papadopoulos, Z., Dikranian, K. T., Dykstra, T., Cao, J., Perrin, R. J., Schwetye, K. E., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-01977-4 · Cited by 22
“This suggests that the pia–arachnoid membrane forming the periarterial space of the MCA allows an exchange of molecules, but not beads, between the periarterial and subarachnoid spaces 26,27 .”
Endres, L. M., Jungblut, M., Divyapicigil, M., Sauer, M., Stigloher, C., Christodoulides, M., Kim, B. J., & Schubert‐Unkmeir, A. (2022) · Fluids and Barriers of the CNS · doi:10.1186/s12987-022-00379-z · Cited by 24
Lin, M.-S. (2023) · Diagnostics · doi:10.3390/diagnostics13020235 · Cited by 21
“The second layer of the meninges, the arachnoid mater, which lies beneath the dura, constitutes the following two layers: the arachnoid barrier cell layer and the arachnoid trabeculae [16].”
BackgroundAquaporin-4 expression in the human choroid plexus
Deffner, F., Gleiser, C., Mattheus, U., Wagner, A., Neckel, P. H., Fallier‐Becker, P., Hirt, B., & Mack, A. F. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04136-1 · Cited by 24
Faropoulos, K., Polia, A., Tsakona, C., Pitaraki, E., Moutafidi, A., Gatzounis, G. D., & Assimakopoulou, M. (2021) · Journal of Molecular Neuroscience · doi:10.1007/s12031-021-01801-1 · Cited by 19
Neuroinflammation-Driven Lymphangiogenesis in CNS Diseases
Hsu, M., Laaker, C. J., Sándor, M., & Fábry, Z. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.683676 · Cited by 20
“Anatomical studies in developing rats revealed the lack of an arachnoid barrier near the cribriform plate (Weller et al., 2018), suggesting that meningeal lymphatics near the cribriform plate may have direct, unrestricted access to the subarachnoid space where prolymphangiogenic factors such as VEGFC may be present du…”
BackgroundSamuels, J. D., Lotstein, M. L., Lehmann, M. L., ELKAHLOUN, A. G., Banerjee, S., & Herkenham, M. A. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02827-5 · Cited by 18
“In addition to the BBB, the blood-cerebrospinal fluid barrier separates blood from the cerebrospinal fluid (CSF) [1], and the arachnoid blood-cerebrospinal fluid barrier separates dural fenestrated blood vessels from the CSF in the subarachnoid space [2].”
BackgroundSubarachnoid space trabeculae architecture
Saboori, P. (2020) · Clinical Anatomy · doi:10.1002/ca.23635 · Cited by 18
“This is evident when the studies of Yamashima and Friede (1984) and Pasquesi (2016) are considered together.”
MethodQiu, F., Habgood, M. D., & Schneider‐Futschik, E. K. (2020) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.0c00098 · Cited by 18
Niche-specific therapeutic targeting of myeloid cells in the central nervous system
Frosch, M., & Prinz, M. (2025) · Immunity · doi:10.1016/j.immuni.2025.03.016 · Cited by 17
Mechanical allodynia in mice with tenascin-X deficiency associated with Ehlers-Danlos syndrome
Okuda‐Ashitaka, E., Kakuchi, Y., Kakumoto, H., Yamanishi, S., Kamada, H., Yoshidu, T., Matsukawa, S., Ogura, N., Uto, S., Minami, T., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-63499-2 · Cited by 17
Metadata
- Authors
- Weller, R. O., Sharp, M. M., Christodoulides, M., Carare, R. O., & Møllgård, K.
- Affiliations
- Southampton General Hospital (GB)
- University of Copenhagen (DK)
- Corresponding author
- Weller, Roy O.
- Venue
- Acta Neuropathologica
- Published
- 2018-01-24
- Volume
- 135
- Issue
- 3
- Pages
- 363-385
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W2786295633
- Cited by
- 222
- References
- 109
- Citations by year
- 2026: 24 · 2025: 25 · 2024: 28 · 2023: 35 · 2022: 22 · 2021: 27 · 2020: 28 · 2019: 22 · 2018: 11
- FWCI
- 2.85
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- Professor Ajay Verma and Biogen
- Vera and Carl Johan Michaelsen Foundation (34077)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
- Keywords
- meninges, leptomeninges, dura mater, arachnoid granulations, cerebrospinal fluid drainage, lymphatic drainage, cribriform plate, meningeal cells, extracellular matrix, Neisseria meningitidis, perivascular spaces, ligand expression
- MeSH terms
- Animals, Humans, Meninges, Rodentia
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