Dysfunctional lymphatic drainage from the central nervous system (CNS) has been linked to neuroinflammatory and neurodegenerative disorders, but our understanding of the lymphatic contribution to CNS fluid autoregulation remains limited. Here, we studied forces that drive the outflow of the cerebrospinal fluid (CSF) into the deep and superficial cervical lymph nodes (dcLN and scLN) and tested how the blockade of lymphatic networks affects CNS fluid homeostasis. Outflow to the dcLN occurred spontaneously in the absence of lymphatic pumping and was coupled to intracranial pressure (ICP), whereas scLN drainage was driven by pumping. Impaired dcLN drainage led to elevated CSF outflow resistance and delayed CSF-to-blood efflux despite the recruitment of the nasal-to-scLN pathway. Fluid regulation was better compensated after scLN obstruction. The dcLN pathway exhibited steady, consistent drainage across conditions, while the nasal-to-scLN pathway was dynamically activated to mitigate perturbances. These findings highlight the complex physiology of CSF homeostasis and lay the groundwork for future studies aimed at assessing and modulating CNS lymphatic function.
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January 08 2025
Differential impact of lymphatic outflow pathways on cerebrospinal fluid homeostasis
Zachary Papadopoulos
,
Zachary Papadopoulos
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
Brain Immunology and Glia (BIG) Center, Washington University in St. Louis
, St. Louis, MO, USA
2Department of Pathology and Immunology,
School of Medicine, Washington University in St. Louis
, St. Louis, MO, USA
3
Neuroscience Graduate Program, School of Medicine, Washington University in St. Louis
, St. Louis, MO, USA
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Leon C.D. Smyth
,
Leon C.D. Smyth
(Investigation, Methodology, Writing - review & editing)
1
Brain Immunology and Glia (BIG) Center, Washington University in St. Louis
, St. Louis, MO, USA
2Department of Pathology and Immunology,
School of Medicine, Washington University in St. Louis
, St. Louis, MO, USA
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Igor Smirnov
,
Igor Smirnov
(Investigation, Methodology, Resources, Supervision)
1
Brain Immunology and Glia (BIG) Center, Washington University in St. Louis
, St. Louis, MO, USA
2Department of Pathology and Immunology,
School of Medicine, Washington University in St. Louis
, St. Louis, MO, USA
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Daniel A. Gibson
,
Daniel A. Gibson
(Writing - review & editing)
1
Brain Immunology and Glia (BIG) Center, Washington University in St. Louis
, St. Louis, MO, USA
2Department of Pathology and Immunology,
School of Medicine, Washington University in St. Louis
, St. Louis, MO, USA
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Jasmin Herz
,
Jasmin Herz
(Resources, Visualization)
1
Brain Immunology and Glia (BIG) Center, Washington University in St. Louis
, St. Louis, MO, USA
2Department of Pathology and Immunology,
School of Medicine, Washington University in St. Louis
, St. Louis, MO, USA
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Jonathan Kipnis
(Conceptualization, Funding acquisition, Supervision, Writing - original draft, Writing - review & editing)
1
Brain Immunology and Glia (BIG) Center, Washington University in St. Louis
, St. Louis, MO, USA
2Department of Pathology and Immunology,
School of Medicine, Washington University in St. Louis
, St. Louis, MO, USA
3
Neuroscience Graduate Program, School of Medicine, Washington University in St. Louis
, St. Louis, MO, USA
Correspondence to Jonathan Kipnis: [email protected]
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Zachary Papadopoulos
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Brain Immunology and Glia (BIG) Center, Washington University in St. Louis
, St. Louis, MO, USA
2Department of Pathology and Immunology,
School of Medicine, Washington University in St. Louis
, St. Louis, MO, USA
3
Neuroscience Graduate Program, School of Medicine, Washington University in St. Louis
, St. Louis, MO, USA
Leon C.D. Smyth
Investigation, Methodology, Writing - review & editing
1
Brain Immunology and Glia (BIG) Center, Washington University in St. Louis
, St. Louis, MO, USA
2Department of Pathology and Immunology,
School of Medicine, Washington University in St. Louis
, St. Louis, MO, USA
Igor Smirnov
Investigation, Methodology, Resources, Supervision
1
Brain Immunology and Glia (BIG) Center, Washington University in St. Louis
, St. Louis, MO, USA
2Department of Pathology and Immunology,
School of Medicine, Washington University in St. Louis
, St. Louis, MO, USA
Daniel A. Gibson
Writing - review & editing
1
Brain Immunology and Glia (BIG) Center, Washington University in St. Louis
, St. Louis, MO, USA
2Department of Pathology and Immunology,
School of Medicine, Washington University in St. Louis
, St. Louis, MO, USA
Jasmin Herz
Resources, Visualization
1
Brain Immunology and Glia (BIG) Center, Washington University in St. Louis
, St. Louis, MO, USA
2Department of Pathology and Immunology,
School of Medicine, Washington University in St. Louis
, St. Louis, MO, USA
Jonathan Kipnis
Conceptualization, Funding acquisition, Supervision, Writing - original draft, Writing - review & editing
1
Brain Immunology and Glia (BIG) Center, Washington University in St. Louis
, St. Louis, MO, USA
2Department of Pathology and Immunology,
School of Medicine, Washington University in St. Louis
, St. Louis, MO, USA
3
Neuroscience Graduate Program, School of Medicine, Washington University in St. Louis
, St. Louis, MO, USA
Correspondence to Jonathan Kipnis: [email protected]
Disclosures: J. Kipnis is a co-founder of Rho Bio, a seed-level company focusing on development of therapies targeting lymphatics. No other disclosures were reported.
Received:
September 22 2024
Revision Received:
December 12 2024
Accepted:
December 23 2024
Online ISSN: 1540-9538
Print ISSN: 0022-1007
Funder(s):
Cure Alzheimer’s Fund
Funder(s):
National Institutes of Health
Funder(s):
National Center for Complementary and Integrative Health
- Award Id(s): R01AT011419
© 2025 Papadopoulos et al.
2025
Papadopoulos et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Exp Med (2025) 222 (2): e20241752.
Article history
Received:
September 22 2024
Revision Received:
December 12 2024
Accepted:
December 23 2024
Citation
Zachary Papadopoulos, Leon C.D. Smyth, Igor Smirnov, Daniel A. Gibson, Jasmin Herz, Jonathan Kipnis; Differential impact of lymphatic outflow pathways on cerebrospinal fluid homeostasis. J Exp Med 3 February 2025; 222 (2): e20241752. doi: https://doi.org/10.1084/jem.20241752
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