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ResearchIn-Press PreviewImmunologyNeuroscience Open Access | 10.1172/JCI182555

Age-dependent brain responses to mechanical stress determine resilience in a chronic lymphatic drainage impairment model

Zachary H. Gursky,1 Zohaib Nisar Khan,2 Sunil Koundal,1 Ankita Bhardwaj,1 Joaquin Caceres Melgarejo,1 Kaiming Xu,1 Xinan Chen,3 Hung-Mo Lin,1 Xianfeng Gu,4 Hedok Lee,1 Jonathan Kipnis,5 Yoav Dori,6 Allen Tannenbaum,4 Laura Santambrogio,2 and Helene Benveniste1

1Department of Anesthesiology, Yale University School of Medicine, New Haven, United States of America

2Department of Radiation Oncology, Weill Cornell Medicine, New York, United States of America

3Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Departments of Computer Science and Applied Mathematics & Statistics, Stony Brook University, Stony Brook, United States of America

5Brain Immunology and Glia (BIG) Center, Department of Pathology and Immunol, Washington University School of Medicine, St. Louis, United States of America

6Division of Cardiology, Jill and Mark Fishman Center for Lymphatic Disorder, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Gursky, Z. in: PubMed | Google Scholar |

1Department of Anesthesiology, Yale University School of Medicine, New Haven, United States of America

2Department of Radiation Oncology, Weill Cornell Medicine, New York, United States of America

3Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Departments of Computer Science and Applied Mathematics & Statistics, Stony Brook University, Stony Brook, United States of America

5Brain Immunology and Glia (BIG) Center, Department of Pathology and Immunol, Washington University School of Medicine, St. Louis, United States of America

6Division of Cardiology, Jill and Mark Fishman Center for Lymphatic Disorder, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Khan, Z. in: PubMed | Google Scholar

1Department of Anesthesiology, Yale University School of Medicine, New Haven, United States of America

2Department of Radiation Oncology, Weill Cornell Medicine, New York, United States of America

3Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Departments of Computer Science and Applied Mathematics & Statistics, Stony Brook University, Stony Brook, United States of America

5Brain Immunology and Glia (BIG) Center, Department of Pathology and Immunol, Washington University School of Medicine, St. Louis, United States of America

6Division of Cardiology, Jill and Mark Fishman Center for Lymphatic Disorder, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Koundal, S. in: PubMed | Google Scholar |

1Department of Anesthesiology, Yale University School of Medicine, New Haven, United States of America

2Department of Radiation Oncology, Weill Cornell Medicine, New York, United States of America

3Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Departments of Computer Science and Applied Mathematics & Statistics, Stony Brook University, Stony Brook, United States of America

5Brain Immunology and Glia (BIG) Center, Department of Pathology and Immunol, Washington University School of Medicine, St. Louis, United States of America

6Division of Cardiology, Jill and Mark Fishman Center for Lymphatic Disorder, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Bhardwaj, A. in: PubMed | Google Scholar

1Department of Anesthesiology, Yale University School of Medicine, New Haven, United States of America

2Department of Radiation Oncology, Weill Cornell Medicine, New York, United States of America

3Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Departments of Computer Science and Applied Mathematics & Statistics, Stony Brook University, Stony Brook, United States of America

5Brain Immunology and Glia (BIG) Center, Department of Pathology and Immunol, Washington University School of Medicine, St. Louis, United States of America

6Division of Cardiology, Jill and Mark Fishman Center for Lymphatic Disorder, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Caceres Melgarejo, J. in: PubMed | Google Scholar

1Department of Anesthesiology, Yale University School of Medicine, New Haven, United States of America

2Department of Radiation Oncology, Weill Cornell Medicine, New York, United States of America

3Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Departments of Computer Science and Applied Mathematics & Statistics, Stony Brook University, Stony Brook, United States of America

5Brain Immunology and Glia (BIG) Center, Department of Pathology and Immunol, Washington University School of Medicine, St. Louis, United States of America

6Division of Cardiology, Jill and Mark Fishman Center for Lymphatic Disorder, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Xu, K. in: PubMed | Google Scholar

1Department of Anesthesiology, Yale University School of Medicine, New Haven, United States of America

2Department of Radiation Oncology, Weill Cornell Medicine, New York, United States of America

3Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Departments of Computer Science and Applied Mathematics & Statistics, Stony Brook University, Stony Brook, United States of America

5Brain Immunology and Glia (BIG) Center, Department of Pathology and Immunol, Washington University School of Medicine, St. Louis, United States of America

6Division of Cardiology, Jill and Mark Fishman Center for Lymphatic Disorder, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Chen, X. in: PubMed | Google Scholar |

1Department of Anesthesiology, Yale University School of Medicine, New Haven, United States of America

2Department of Radiation Oncology, Weill Cornell Medicine, New York, United States of America

3Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Departments of Computer Science and Applied Mathematics & Statistics, Stony Brook University, Stony Brook, United States of America

5Brain Immunology and Glia (BIG) Center, Department of Pathology and Immunol, Washington University School of Medicine, St. Louis, United States of America

6Division of Cardiology, Jill and Mark Fishman Center for Lymphatic Disorder, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Lin, H. in: PubMed | Google Scholar

1Department of Anesthesiology, Yale University School of Medicine, New Haven, United States of America

2Department of Radiation Oncology, Weill Cornell Medicine, New York, United States of America

3Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Departments of Computer Science and Applied Mathematics & Statistics, Stony Brook University, Stony Brook, United States of America

5Brain Immunology and Glia (BIG) Center, Department of Pathology and Immunol, Washington University School of Medicine, St. Louis, United States of America

6Division of Cardiology, Jill and Mark Fishman Center for Lymphatic Disorder, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Gu, X. in: PubMed | Google Scholar

1Department of Anesthesiology, Yale University School of Medicine, New Haven, United States of America

2Department of Radiation Oncology, Weill Cornell Medicine, New York, United States of America

3Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Departments of Computer Science and Applied Mathematics & Statistics, Stony Brook University, Stony Brook, United States of America

5Brain Immunology and Glia (BIG) Center, Department of Pathology and Immunol, Washington University School of Medicine, St. Louis, United States of America

6Division of Cardiology, Jill and Mark Fishman Center for Lymphatic Disorder, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Lee, H. in: PubMed | Google Scholar

1Department of Anesthesiology, Yale University School of Medicine, New Haven, United States of America

2Department of Radiation Oncology, Weill Cornell Medicine, New York, United States of America

3Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Departments of Computer Science and Applied Mathematics & Statistics, Stony Brook University, Stony Brook, United States of America

5Brain Immunology and Glia (BIG) Center, Department of Pathology and Immunol, Washington University School of Medicine, St. Louis, United States of America

6Division of Cardiology, Jill and Mark Fishman Center for Lymphatic Disorder, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Kipnis, J. in: PubMed | Google Scholar

1Department of Anesthesiology, Yale University School of Medicine, New Haven, United States of America

2Department of Radiation Oncology, Weill Cornell Medicine, New York, United States of America

3Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Departments of Computer Science and Applied Mathematics & Statistics, Stony Brook University, Stony Brook, United States of America

5Brain Immunology and Glia (BIG) Center, Department of Pathology and Immunol, Washington University School of Medicine, St. Louis, United States of America

6Division of Cardiology, Jill and Mark Fishman Center for Lymphatic Disorder, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Dori, Y. in: PubMed | Google Scholar

1Department of Anesthesiology, Yale University School of Medicine, New Haven, United States of America

2Department of Radiation Oncology, Weill Cornell Medicine, New York, United States of America

3Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Departments of Computer Science and Applied Mathematics & Statistics, Stony Brook University, Stony Brook, United States of America

5Brain Immunology and Glia (BIG) Center, Department of Pathology and Immunol, Washington University School of Medicine, St. Louis, United States of America

6Division of Cardiology, Jill and Mark Fishman Center for Lymphatic Disorder, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Tannenbaum, A. in: PubMed | Google Scholar

1Department of Anesthesiology, Yale University School of Medicine, New Haven, United States of America

2Department of Radiation Oncology, Weill Cornell Medicine, New York, United States of America

3Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Departments of Computer Science and Applied Mathematics & Statistics, Stony Brook University, Stony Brook, United States of America

5Brain Immunology and Glia (BIG) Center, Department of Pathology and Immunol, Washington University School of Medicine, St. Louis, United States of America

6Division of Cardiology, Jill and Mark Fishman Center for Lymphatic Disorder, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Santambrogio, L. in: PubMed | Google Scholar |

1Department of Anesthesiology, Yale University School of Medicine, New Haven, United States of America

2Department of Radiation Oncology, Weill Cornell Medicine, New York, United States of America

3Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Departments of Computer Science and Applied Mathematics & Statistics, Stony Brook University, Stony Brook, United States of America

5Brain Immunology and Glia (BIG) Center, Department of Pathology and Immunol, Washington University School of Medicine, St. Louis, United States of America

6Division of Cardiology, Jill and Mark Fishman Center for Lymphatic Disorder, Children’s Hospital of Philadelphia, Philadelphia, United States of America

Find articles by Benveniste, H. in: PubMed | Google Scholar |

Published July 15, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI182555.
Copyright © 2025, Gursky et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 15, 2025 - Version history
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Abstract

The outflow of 'dirty' brain fluids from the glymphatic system drains via the meningeal lymphatic vessels to the lymph nodes in the neck, primarily the deep cervical lymph nodes (dcLN). However, it is unclear whether dcLN drainage is essential for normal cerebral homeostasis. Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and computational fluid dynamics, we studied the impact of long-term mechanical stress from compromised dcLN drainage on brain solute and fluid outflow in anesthetized rats. We found that in young, but not middle-aged rats, impairment of dcLN drainage was linked to moderately increased intracranial pressure and the emergence of extracranial peri-venous drainage, with no evidence of hydrocephalus at any age. Surprisingly, both age groups showed enhanced brain solute clearance despite reduced glymphatic influx. CSF proteomic analysis revealed cellular stress in the form of low-grade inflammation, and up-regulation of pathways associated with neurodegeneration and blood brain barrier leakage in the rats with impaired lymphatic drainage. Our findings highlight that dcLN drainage is indeed a prerequisite for normal cerebral homeostasis in the rat and reveal the brain’s age-dependent compensatory responses to chronic impairment of its lymphatic drainage pathways.

Supplemental material

View Supplemental Table 2 shows the extended data for the proteomics analysis

View Supplemental Table 3 shows the extended data for the metabolomic and lipidomics analysis.

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Version history
  • Version 1 (July 15, 2025): In-Press Preview
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