One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment1,2,3, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood4,5,6. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system 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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We thank S. Smith for editing the manuscript; V. Engelhard for initial discussions and suggestions on lymphatic endothelial cell specific markers. We also thank the members of the Kipnis laboratory, Brain Immunology and Glia (BIG) center, and the Department of Neuroscience at the University of Virginia (especially J. Lukens) for their valuable comments during multiple discussions of this work. L. Holland and B. Lopes provided the human samples. This work was funded by “Fondation pour la Recherche Medicale” to A.L. and by The National Institutes of Health (R01AG034113 and R01NS061973) to J.K.
Extended data figures
Adult mice were injected i.v. with DyLight 488 lectin prior to euthanasia. Meninges were harvested and stained for lymphatic endothelial cells (Lyve-1). A 3D reconstruction of both the blood vasculature (green) and the meningeal lymphatic vessels (red) using IMARIS software are presented.
Meninges and diaphragm from adult mice were harvested and stained for lymphatic endothelial cells (Lyve-1). A 3D reconstruction of the lymphatic network using IMARIS software is presented.
Adult mice were injected i.v. with fluorescein and i.c.v. with QDot655. The superior sagittal sinus was imaged intravitally by 2-photon microscope under a thinned skull. The CSF-filled vessel (red) is visible between the sinus (left) and the CSF (right).
Adult mice were injected i.v. with QDot655 (red) and i.c.v. with Alexa488 conjugated anti-Lyve-1 antibody (green). The superior sagittal sinus was imaged intravitally by 2-photon microscope under a thinned skull and the surface was reconstructed using IMARIS software. The signal from the remaining skull (blue) was recorded.
Adult mice were injected i.v. with fluorescein and i.c.v. with QDot655. The superior sagittal sinus was imaged intravitally by 2-photon microscope under a thinned skull. The blood flow in the sinus (green, left) appears faster than the one in the meningeal lymphatic vessels (red, right). The flow inside of the lymphatic vessels appears unidirectional.