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

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

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
State	Published - Dec 3 2025

Keywords

CSF drainage
glymphatics
immune surveillance
meningeal lymphatics
meninges
neuroimmunology

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10.1016/j.neuron.2025.10.036

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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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title = "Resolving the mysteries of brain clearance and immune surveillance",

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.",

keywords = "CSF drainage, glymphatics, immune surveillance, meningeal lymphatics, meninges, neuroimmunology",

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

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s).",

year = "2025",

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

language = "English",

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Kipnis, J, Benveniste, H, Eichmann, A, Thomas, JL, Reich, DS, Lewis, LD, Tsai, LH, 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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T1 - Resolving the mysteries of brain clearance and immune surveillance

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

KW - neuroimmunology

UR - https://www.scopus.com/pages/publications/105023439274

U2 - 10.1016/j.neuron.2025.10.036

DO - 10.1016/j.neuron.2025.10.036

M3 - Review article

C2 - 41289996

AN - SCOPUS:105023439274

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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