Structural and functional features of central nervous system lymphatic vessels
Open accessAbstract
One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
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Lymphatic vessels draining from CSF to neck lymph nodes were first detected in walls of dural venous sinuses in 2015.
“In 2015, lymphatic vessels draining from CSF to neck lymph nodes were for the first time detected in walls of dural venous sinuses (51, 52).”
From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [52]
Meningeal lymphatic vessels in the dura drain brain interstitial CSF.
“two other groups reported that classical lymphatic vessels draining brain interstitial CSF might also be identified in the dura – the fibrous external layer of the meningeal membranes (39, 40).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [39]
The glymphatic and meningeal lymphatic systems are connected, and CSF tracers exit the CNS via meningeal lymphatic vessels, especially ventral lymph vessels draining to cervical lymph nodes.
“Yet the glymphatic and meningeal lymphatic systems are clearly connected: CSF tracers can exit the CNS via the meningeal lymphatic vessels, particularly by way of the lymph vessels draining the ventral aspect of the brain draining to the cervical lymph nodes (39, 40, 42).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [39]
Louveau et al showed active lymphatic vessels connecting the CNS to the lymphatic system that may act as a conduit for neuroimmunological dysfunction.
“the recent groundbreaking work by Louveau et al (2015) showing active lymphatic vessels connecting the CNS to the lymphatic system that may possibly act as a conduit for neuroimmunological dysfunction.”
From The Role of the Immune System in Autism Spectrum Disorder (2017) · cites this paper as Louveau et al (2015)
Initial lymphatics at the dorsal brain meninges are important for cerebrospinal fluid drainage.
“These results emphasize the importance of initial lymphatics at the dorsal brain meninges in CSF drainage5,12,18.”
From Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy (2021) · cites this paper as [18]
The dural compartment of the meninges is closest to the skull and is predominantly composed of fibroblasts, but also includes fenestrated blood vasculature, an elaborate lymphatic system, and immune cells distinct from the CNS.
“The dural compartment of the meninges, closest to the skull, is predominantly composed of fibroblasts, but also includes fenestrated blood vasculature, an elaborate lymphatic system, as well as immune cells which are distinct from the CNS.”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Louveau et al., 2015
CSF macromolecules likely reach the dura by traversing the arachnoid layer underlying the dural sinuses.
“CSF macromolecules are likely reaching the dura by traversing the arachnoid layer underlying the dural sinuses17.”
From Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons (2020) · cites this paper as [17]
The extent of enhancing tissue within parasagittal dura does not resemble previously reported appearance of true dural lymphatic vessels (tubular-shaped, sub-millimeter, near venous sinus wall) nor classical MRI appearance of arachnoid granulations bulging into venous sinuses.
“The extent of enhancing tissue within parasagittal dura does not resemble the previously reported appearance of true dural lymphatic vessels, which are tubular-shaped structures of sub-millimeter cross-sectional diameter near the venous sinus wall3,4,11, and also far from the classical MRI appearance of arachnoid granulations bulging into venous sinuses12.”
From Cerebrospinal fluid tracer efflux to parasagittal dura in humans (2020) · cites this paper as [4]
True lymphatic vessels reside within the dura mater.
“true lymphatic vessels were shown to reside within the dura mater3,4”
From Cerebrospinal fluid tracer efflux to parasagittal dura in humans (2020) · cites this paper as [4]
It seems plausible that molecules within parasagittal dura structures may reach adjacent lymphatic vessels, and perhaps also vice versa.
“it seems plausible that molecules within parasagittal dura structures may well reach adjacent lymphatic vessels, and perhaps also vice versa”
From Cerebrospinal fluid tracer efflux to parasagittal dura in humans (2020) · cites this paper as [4]
Lymphatics have been discovered in the dura mater and just outside holes in the skull bone.
“Although the CNS parenchyma does not have a conventional lymphatic drainage system (3), lymphatics have been discovered in the dura mater and just outside holes in the skull bone (4-9).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [4]
Antigen drainage from the dura mater occurs by way of lymphatic vessels traversing the dura mater and draining to the deep cervical lymph nodes.
“Antigen drainage from the dura mater occurs in a similar fashion by way of lymphatic vessels traversing the dura mater and draining to the deep cervical lymph nodes (4, 5, 64).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [4]
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- Authors
- Louveau, A., Smirnov, I., Keyes, T. J., Eccles, J. D., Rouhani, S. J., Peske, J. D., Derecki, N. C., Castle, D., Mandell, J. W., Lee, K. S., Harris, T. H., & Kipnis, J.
- Affiliations
- University of Virginia (US)
- Corresponding author
- Louveau, Antoine
- Kipnis, Jonathan
- ORCID
- Venue
- Nature
- Published
- 2015-06-01
- Volume
- 523
- Issue
- 7560
- Pages
- 337-341
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4506234
- OpenAlex
- W1588685142
- Cited by
- 4,413
- References
- 30
- Citations by year
- 2026: 391 · 2025: 399 · 2024: 423 · 2023: 417 · 2022: 429 · 2021: 435 · 2020: 365 · 2019: 376 · 2018: 367 · 2017: 338 · 2016: 323 · 2015: 146 · 2014: 2
- FWCI
- 170.91
- Type
- journal article
- Language
- en
- Update notices
- correction (2016-02-24)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG034113)
- National Cancer Institute (P30CA044579)
- National Institute of Allergy and Infectious Diseases (T32AI007496)
- National Institute of Neurological Disorders and Stroke (R01NS061973)
- Topics
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- meningeal lymphatic drainage, cerebrospinal fluid, lymphatic endothelial cells, dural venous sinuses, neuroimmunology, neuroinflammation, neurodegenerative diseases, deep cervical lymph nodes
- MeSH terms
- Animals, Central Nervous System, Cranial Sinuses, Female, Humans, Immune Tolerance, Immunologic Surveillance, Male, Meninges, Mice, Inbred C57BL, T-Lymphocytes, Lymphatic Vessels
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