CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature.
Antoine Louveau,Jasmin Herz,Maria Nordheim Alme,Andrea Francesca Salvador,Michael Q. Dong,Kenneth E. Viar,S. Grace Herod,James Knopp,Joshua C. Setliff,Alexander L. Lupi,Sandro Da Mesquita,Elizabeth L. Frost,Alban Gaultier,Tajie H. Harris,Rui Cao,Song Hu,John R. Lukens,Igor Smirnov,Christopher C. Overall,Guillermo Oliver,Jonathan Kipnis +20 more
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TLDR
It is demonstrated that meningeal lymphatics drain CSF-derived macromolecules and immune cells and play a key role in regulating neuroinflammation and may represent a new therapeutic target for multiple sclerosis.Abstract:
Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfill two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.read more
Citations
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Journal ArticleDOI
Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid
Ji-Hoon Ahn,Hyunsoo Cho,Jun-Hee Kim,Shin Heun Kim,Je-Seok Ham,Intae Park,Sang Heon Suh,Seon Pyo Hong,Joo Hye Song,Young-Kwon Hong,Yong Jeong,Sung-Hong Park,Gou Young Koh +12 more
TL;DR: The importance of meningeal lymphatic vessels in the basal part of the skull for CSF clearance is revealed by visualizing their distinct anatomical location and characterizing their specialized morphological features, which facilitate the uptake and drainage of CSF.
Journal ArticleDOI
The Lymphatic Vasculature in the 21st Century: Novel Functional Roles in Homeostasis and Disease
TL;DR: It is proposed that subtle asymptomatic alterations in lymphatic vascular function could underlie the variability seen in the body's response to a wide range of human diseases.
Journal ArticleDOI
Brain immunology and immunotherapy in brain tumours
TL;DR: How advances in the understanding of the immune system within the brain have implications for the successful implementation of immunotherapy to treat brain tumours is discussed, despite challenges such as effective delivery, target specificity and intratumour heterogeneity.
Journal ArticleDOI
VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours
Eric Song,Tianyang Mao,Huiping Dong,Ligia Simoes Braga Boisserand,Salli Antila,Marcus Bosenberg,Kari Alitalo,Jean-Leon Thomas,Jean-Leon Thomas,Akiko Iwasaki,Akiko Iwasaki,Akiko Iwasaki +11 more
TL;DR: In a mouse model of glioblastoma, treatment with VEGF-C increases lymphatic drainage in the central nervous system and improves the immune response, suggesting that modulating meningeal lymphatics could enhance checkpoint inhibitor therapy.
Journal ArticleDOI
The Meningeal Lymphatic System: A New Player in Neurophysiology.
TL;DR: The meningeal lymphatic system can be viewed as a novel player in neurophysiology by altering the accessibility of CSF-borne immune neuromodulators to the brain parenchyma, thereby altering their effects on the brain.
References
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A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.
Jeffrey J. Iliff,Minghuan Wang,Minghuan Wang,Yonghong Liao,Benjamin A. Plogg,Weiguo Peng,Georg Andreas Gundersen,Helene Benveniste,G. Edward Vates,Rashid Deane,Steven A. Goldman,Erlend A. Nagelhus +11 more
TL;DR: An anatomically distinct clearing system in the brain that serves a lymphatic-like function is described and may have relevance for understanding or treating neurodegenerative diseases that involve the mis-accumulation of soluble proteins, such as amyloid β in Alzheimer's disease.
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Structural and functional features of central nervous system lymphatic vessels
Antoine Louveau,Igor Smirnov,Timothy J. Keyes,Jacob D. Eccles,Sherin J. Rouhani,J. David Peske,Noël C. Derecki,David Castle,James Mandell,Kevin S. Lee,Tajie H. Harris,Jonathan Kipnis +11 more
TL;DR: In searching for T-cell gateways into and out of the meninges, functional lymphatic vessels lining the dural sinuses are discovered, which may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
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Immunopathology of multiple sclerosis
TL;DR: The current understanding of multiple sclerosis immunopathology is discussed, long-standing hypotheses regarding the role of the immune system in the disease are evaluated, and key questions that are still unanswered are delineated.
Journal ArticleDOI
Prox1 Function Is Required for the Development of the Murine Lymphatic System
TL;DR: It is reported that the homeobox gene Prox1 is expressed in a subpopulation of endothelial cells that by budding and sprouting give rise to the lymphatic system, suggesting that unidentified guidance signals regulate this process.
Journal ArticleDOI
A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules
Aleksanteri Aspelund,Salli Antila,Steven T. Proulx,Tine V. Karlsen,Sinem Karaman,Michael Detmar,Helge Wiig,Kari Alitalo +7 more
TL;DR: The presence of a lymphatic vessel network in the dura mater of the mouse brain is discovered and it is shown that these dural lymphatic vessels are important for the clearance of macromolecules from the brain.
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