Resolving the mysteries of brain clearance and immune surveillance

Jonathan Kipnis; Helene Benveniste; Anne Eichmann; Jean-Leon Thomas; Daniel S. Reich; Laura D. Lewis; Li-Huei Tsai; Antoine Drieu; Erik N. T. P. Bakker; Douglas H. Kelley; Iben Lundgaard; Humberto Mestre; Benedikt Zott; Per Kristian Eide; Matthias J. P. van Osch; Susanne J. van Veluw; Jeffrey Iliff; Andrew C. Yang; Laura Santambrogio; Sandro da Mesquita; Richard Daneman; Justin Rustenhoven; Steven A. Goldman; Maiken Nedergaard

doi:10.1016/j.neuron.2025.10.036

Resolving the mysteries of brain clearance and immune surveillance

Jonathan Kipnis^*
, Helene Benveniste
, Anne Eichmann
, Jean-Leon Thomas
, Daniel S. Reich
, Laura D. Lewis
, Li-Huei Tsai
, Antoine Drieu
, Erik N. T. P. Bakker
, Douglas H. Kelley
, Iben Lundgaard
, Humberto Mestre
, Benedikt Zott
, Per Kristian Eide
, Matthias J. P. van Osch
, Susanne J. van Veluw
, Jeffrey Iliff
, Andrew C. Yang
, Laura Santambrogio
, Sandro da Mesquita

Richard Daneman, Justin Rustenhoven, Steven A. Goldman, Maiken Nedergaard^*

^*Corresponding author for this work

Washington University St. Louis
Yale University
PARCC - Paris-Centre de Recherche Cardiovasculaire
Institut du Cerveau et de la Moelle Épinière
National Institutes of Health
Massachusetts Institute of Technology
Massachusetts General Hospital
Université Paris Cité
University of Amsterdam
Amsterdam UMC
University of Rochester
Lund University
Harvard University
Technical University of Munich
University of Oslo
Leiden University
University of Edinburgh
VA Puget Sound Health Care System
University of Washington
Gladstone Institutes
University of California at San Francisco
Cornell University
Mayo Clinic College of Medicine and Science
University of California at San Diego
The University of Auckland
University of Copenhagen

Research output: Contribution to journal › Review article › Academic › peer-review

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Abstract

Recent advances are transforming our understanding of brain fluid dynamics, highlighting cerebrospinal fluid (CSF) flow as a key process in brain waste clearance. While debates persist regarding its anatomical pathways and regulatory mechanisms, certain core principles have become widely accepted. CSF influx occurs primarily along periarterial spaces, solute clearance follows multiple routes, and glymphatic and meningeal lymphatic systems are functionally connected. Brain clearance is influenced by vascular pulsation, neural activity, and sleep. Immune cells at brain-border niches both monitor solute efflux and modulate flow, linking brain clearance to neuroimmune interactions. A deeper understanding of brain clearance could unlock new therapeutic avenues for autoimmune, neurodegenerative, neoplastic, and psychiatric disorders.

Original language	English
Pages (from-to)	3908-3923
Number of pages	16
Journal	Neuron
Volume	113
Issue number	23
DOIs	https://doi.org/10.1016/j.neuron.2025.10.036
Publication status	Published - 3 Dec 2025

Keywords

CSF drainage
glymphatics
immune surveillance
meningeal lymphatics
meninges
neuroimmunology

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10.1016/j.neuron.2025.10.036

Resolving-the-mysteries-of-brain-clearance-and-immune-surveillance.pdfFinal published version, 3.66 MBLicence: CC BY

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Kipnis, J., Benveniste, H., Eichmann, A., Thomas, J.-L., Reich, D. S., Lewis, L. D., Tsai, L.-H., Drieu, A., Bakker, E. N. T. P., Kelley, D. H., Lundgaard, I., Mestre, H., Zott, B., Eide, P. K., van Osch, M. J. P., van Veluw, S. J., Iliff, J., Yang, A. C., Santambrogio, L., ... Nedergaard, M. (2025). Resolving the mysteries of brain clearance and immune surveillance. Neuron, 113(23), 3908-3923. https://doi.org/10.1016/j.neuron.2025.10.036

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abstract = "Recent advances are transforming our understanding of brain fluid dynamics, highlighting cerebrospinal fluid (CSF) flow as a key process in brain waste clearance. While debates persist regarding its anatomical pathways and regulatory mechanisms, certain core principles have become widely accepted. CSF influx occurs primarily along periarterial spaces, solute clearance follows multiple routes, and glymphatic and meningeal lymphatic systems are functionally connected. Brain clearance is influenced by vascular pulsation, neural activity, and sleep. Immune cells at brain-border niches both monitor solute efflux and modulate flow, linking brain clearance to neuroimmune interactions. A deeper understanding of brain clearance could unlock new therapeutic avenues for autoimmune, neurodegenerative, neoplastic, and psychiatric disorders.",

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year = "2025",

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doi = "10.1016/j.neuron.2025.10.036",

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Kipnis, J, Benveniste, H, Eichmann, A, Thomas, J-L, Reich, DS, Lewis, LD, Tsai, L-H, Drieu, A, Bakker, ENTP, Kelley, DH, Lundgaard, I, Mestre, H, Zott, B, Eide, PK, van Osch, MJP, van Veluw, SJ, Iliff, J, Yang, AC, Santambrogio, L, da Mesquita, S, Daneman, R, Rustenhoven, J, Goldman, SA & Nedergaard, M 2025, 'Resolving the mysteries of brain clearance and immune surveillance', Neuron, vol. 113, no. 23, pp. 3908-3923. https://doi.org/10.1016/j.neuron.2025.10.036

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AU - Kipnis, Jonathan

AU - Benveniste, Helene

AU - Eichmann, Anne

AU - Thomas, Jean-Leon

AU - Reich, Daniel S.

AU - Lewis, Laura D.

AU - Tsai, Li-Huei

AU - Drieu, Antoine

AU - Bakker, Erik N. T. P.

AU - Kelley, Douglas H.

AU - Lundgaard, Iben

AU - Mestre, Humberto

AU - Zott, Benedikt

AU - Eide, Per Kristian

AU - van Osch, Matthias J. P.

AU - van Veluw, Susanne J.

AU - Iliff, Jeffrey

AU - Yang, Andrew C.

AU - Santambrogio, Laura

AU - da Mesquita, Sandro

AU - Daneman, Richard

AU - Rustenhoven, Justin

AU - Goldman, Steven A.

AU - Nedergaard, Maiken

PY - 2025/12/3

Y1 - 2025/12/3

N2 - Recent advances are transforming our understanding of brain fluid dynamics, highlighting cerebrospinal fluid (CSF) flow as a key process in brain waste clearance. While debates persist regarding its anatomical pathways and regulatory mechanisms, certain core principles have become widely accepted. CSF influx occurs primarily along periarterial spaces, solute clearance follows multiple routes, and glymphatic and meningeal lymphatic systems are functionally connected. Brain clearance is influenced by vascular pulsation, neural activity, and sleep. Immune cells at brain-border niches both monitor solute efflux and modulate flow, linking brain clearance to neuroimmune interactions. A deeper understanding of brain clearance could unlock new therapeutic avenues for autoimmune, neurodegenerative, neoplastic, and psychiatric disorders.

AB - Recent advances are transforming our understanding of brain fluid dynamics, highlighting cerebrospinal fluid (CSF) flow as a key process in brain waste clearance. While debates persist regarding its anatomical pathways and regulatory mechanisms, certain core principles have become widely accepted. CSF influx occurs primarily along periarterial spaces, solute clearance follows multiple routes, and glymphatic and meningeal lymphatic systems are functionally connected. Brain clearance is influenced by vascular pulsation, neural activity, and sleep. Immune cells at brain-border niches both monitor solute efflux and modulate flow, linking brain clearance to neuroimmune interactions. A deeper understanding of brain clearance could unlock new therapeutic avenues for autoimmune, neurodegenerative, neoplastic, and psychiatric disorders.

KW - CSF drainage

KW - glymphatics

KW - immune surveillance

KW - meningeal lymphatics

KW - meninges

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DO - 10.1016/j.neuron.2025.10.036

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SN - 0896-6273

VL - 113

SP - 3908

EP - 3923

JO - Neuron

JF - Neuron

IS - 23

ER -

Resolving the mysteries of brain clearance and immune surveillance

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Keywords

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