Functional characterization of the dural sinuses as a neuroimmune interface
Open accessAbstract
Despite the established dogma of central nervous system (CNS) immune privilege, neuroimmune interactions play an active role in diverse neurological disorders. However, the precise mechanisms underlying CNS immune surveillance remain elusive; particularly, the anatomical sites where peripheral adaptive immunity can sample CNS-derived antigens and the cellular and molecular mediators orchestrating this surveillance. Here, we demonstrate that CNS-derived antigens in the cerebrospinal fluid (CSF) accumulate around the dural sinuses, are captured by local antigen-presenting cells, and are presented to patrolling T cells. This surveillance is enabled by endothelial and mural cells forming the sinus stromal niche. T cell recognition of CSF-derived antigens at this site promoted tissue resident phenotypes and effector functions within the dural meninges. These findings highlight the critical role of dural sinuses as a neuroimmune interface, where brain antigens are surveyed under steady-state conditions, and shed light on age-related dysfunction and neuroinflammatory attack in animal models of multiple sclerosis.
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The dura mater is the epicenter of immune surveillance in the brain, where macrophages present antigens to T cells to induce immune responses.
“The dura mater is considered the epicenter of immune surveillance in the brain, where macrophages present antigens to T cells to induce immune responses (66).”
From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [66]
During aging, the meninges undergo a shift towards pro-inflammatory immune responses, characterized by an increased number of T cells and B cells.
“During aging, the meninges undergo a shift towards pro-inflammatory immune responses, characterized by an increased number of T cells and B cells.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [680]
In 13-14-month-old 5xFAD mice, dorsal meningeal lymphatic deterioration coincides with a significant rise in amyloid-beta deposition throughout the meninges, including along blood and lymphatic vessels.
“The deterioration of the lymphatic vasculature at the dorsal meninges observed in 13–14-month-old 5xFAD mice was accompanied by a significant increase in Aβ deposition throughout the meninges (Extended Data Fig. 1c–e), with extensive Aβ deposition along the blood and lymphatic vasculature (Extended Data Fig. 1a, insets) at anatomical locations previously shown as ‘hot spots’ along meningeal lymph”
From Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy (2021) · cites this paper as [13]
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Self-citationDeep Amino Acid Sequencing of Native Brain GABAA Receptors Using High-Resolution Mass Spectrometry
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Self-citationMartin‐Blondel, G., Pignolet, B., Tietz, S., Yshii, L., Gebauer, C., Périnat, T., Weddingen, I. V., Blatti, C., Engelhardt, B., & Liblau, R. (2015) · European Journal of Immunology · doi:10.1002/eji.201545632 · Cited by 58 · see citing works
Adventitial Cuffs: Regional Hubs for Tissue Immunity
Dahlgren, M. W., & Molofsky, A. B. (2019) · Trends in Immunology · doi:10.1016/j.it.2019.08.002 · Cited by 58 · see citing works
Cannula Implantation into the Cisterna Magna of Rodents
Xavier, A. L. R., Hauglund, N. L., von Holstein‐Rathlou, S., et al. (2018) · Journal of Visualized Experiments · doi:10.3791/57378-v · Cited by 27 · see citing works
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Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
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Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma
Cugurra, A., Mamuladze, T., Rustenhoven, J., Dykstra, T., Beroshvili, G., Greenberg, Z. J., Baker, W., Papadopoulos, Z., Drieu, A., Blackburn, S., et al. (2021) · Science · doi:10.1126/science.abf7844 · Cited by 681 · see citing works
Self-citationHeterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders
Brioschi, S., Wang, W.-L., Peng, V., Wang, M., Shchukina, I., Greenberg, Z. J., Bando, J. K., Jaeger, N., Czepielewski, R. S., Swain, A., et al. (2021) · Science · doi:10.1126/science.abf9277 · Cited by 472 · see citing works
Self-citationMeningeal lymphatics affect microglia responses and anti-Aβ immunotherapy
Da Mesquita, S., Papadopoulos, Z., Dykstra, T., Brase, L., Farias, F. G., Wall, M., Jiang, H., Kodira, C. D., de Lima, K. A., Herz, J., et al. (2021) · Nature · doi:10.1038/s41586-021-03489-0 · Cited by 431 · see citing works
Self-citationNeuromodulation by the immune system: a focus on cytokines
Salvador, A. F., de Lima, K. A., & Kipnis, J. (2021) · Nature Reviews Immunology · doi:10.1038/s41577-021-00508-z · Cited by 389 · see citing works
Self-citationEmerging roles of innate and adaptive immunity in Alzheimer’s disease
Chen, X., & Holtzman, D. M. (2022) · Immunity · doi:10.1016/j.immuni.2022.10.016 · Cited by 297 · see citing works
Da Mesquita, S., Herz, J., Wall, M., Dykstra, T., de Lima, K. A., Norris, G. T., Dabhi, N., Kennedy, T., Baker, W., & Kipnis, J. (2021) · Science Advances · doi:10.1126/sciadv.abe4601 · Cited by 172 · see citing works
Self-citationLiving on the Edge of the CNS: Meninges Cell Diversity in Health and Disease
Derk, J., Jones, H. E., Como, C., Pawlikowski, B., & Siegenthaler, J. A. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.703944 · Cited by 120 · see citing works
The Gut Microbiome as a Regulator of the Neuroimmune Landscape
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Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model
Wu, X., Miller, J. A., Lee, B. T. K., Wang, Y., & Ruedl, C. (2025) · Science Advances · doi:10.1126/sciadv.adq6038 · Cited by 67 · see citing works
“The dura mater is considered the epicenter of immune surveillance in the brain, where macrophages present antigens to T cells to induce immune responses ( 66 ).”
Immunological defense of CNS barriers against infections
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Mechanisms of myeloid cell entry to the healthy and diseased central nervous system
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Role of Dendritic Cells in Viral Brain Infections
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Impact of aging on meningeal gene expression
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<scp>CNS</scp> macrophage contributions to myelin health
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- Authors
- Rustenhoven, J., Drieu, A., Mamuladze, T., de Lima, K. A., Dykstra, T., Wall, M., Papadopoulos, Z., Kanamori, M., Salvador, A. F., Baker, W., Lemieux, M., Da Mesquita, S., Cugurra, A., Fitzpatrick, J., Sviben, S., Kossina, R., Bayguinov, P., Townsend, R. R., Zhang, Q., Erdmann-Gilmore, P., Smirnov, I., Lopes, M.-B., Herz, J., & Kipnis, J.
- Affiliations
- Washington University in St. Louis (US)
- University of Virginia (US)
- Johannes Gutenberg University Mainz (DE)
- Corresponding author
- Rustenhoven, Justin
- Kipnis, Jonathan
- ORCID
- Rustenhoven, Justin
- Drieu, Antoine
- Mamuladze, Tornike
- de Lima, Kalil Alves
- Dykstra, Taitea
- Papadopoulos, Zachary
- Salvador, Andrea Francesca
- Lemieux, Mackenzie
- Da Mesquita, Sandro
- Cugurra, Andrea
- Fitzpatrick, James
- Sviben, Sanja
- Kossina, Ross
- Bayguinov, Peter
- Townsend, Reid R.
- Zhang, Qiang
- Erdmann-Gilmore, Petra
- Smirnov, Igor
- Lopes, Maria-Beatriz
- Herz, Jasmin
- Kipnis, Jonathan
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-02
- Volume
- 184
- Issue
- 4
- Pages
- 1000-1016.e27
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8487654
- OpenAlex
- W3125753820
- Cited by
- 685
- References
- 83
- Citations by year
- 2026: 128 · 2025: 120 · 2024: 144 · 2023: 116 · 2022: 113 · 2021: 64
- FWCI
- 43.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Funders
- Washington University School of Medicine in St. Louis
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- dural venous sinuses, neuroimmune interface, antigen-presenting cells, T cell recognition, multiple sclerosis, neuroinflammation
- MeSH terms
- Animals, Antigen-Presenting Cells, Antigens, Cranial Sinuses, Dura Mater, Female, Homeostasis, Humans, Immunity, Male, Mice, Inbred C57BL, Phenotype, T-Lymphocytes, Cellular Senescence, Stromal Cells, Antigen Presentation, Mice, Chemokine CXCL12
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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