Understanding the functions and relationships of the glymphatic system and meningeal lymphatics
Antoine Louveau, … , Maiken Nedergaard, Jonathan Kipnis
Antoine Louveau, … , Maiken Nedergaard, Jonathan Kipnis
Published September 1, 2017
Citation Information: J Clin Invest. 2017;127(9):3210-3219. https://doi.org/10.1172/JCI90603.
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Understanding the functions and relationships of the glymphatic system and meningeal lymphatics

Abstract

Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges to the peripheral (CNS-draining) lymph nodes. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems.

Authors

Antoine Louveau, Benjamin A. Plog, Salli Antila, Kari Alitalo, Maiken Nedergaard, Jonathan Kipnis

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Figure 2

Glymphatic and lymphatic drainage pathways from the CNS to the cervical lymph nodes.

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Glymphatic and lymphatic drainage pathways from the CNS to the cervical ...
(A) Schematic illustration of the meningeal lymphatic vessel system in mouse cranium. The dural lymphatic vessels align with dural blood vessels and cranial nerves and exit the cranium via the foramina together with the venous sinuses, arteries, and cranial nerves. Some lymphatic vessels are also found traversing the cribriform plate with the olfactory nerves. Tracers injected into either brain parenchyma or SAS drain via the dural lymphatic vessels into dcLNs located next to the jugular vein. (B) Close-up view of ISF and CSF circulation. The perivascular glymphatic drainage system transports CSF and solutes into the brain via a periarterial pathway, whereas ISF and solutes exit the brain via the perivenous glymphatic pathway. CSF can enter the venous system via arachnoid granulations, and CSF macromolecules and immune cells are transported mainly along the dural lymphatic vessels into the lymph nodes and extracranial systemic circulation. (C) Out-of-CNS drainage routes for antigens and antigen-presenting cells (APCs). Antigens and APCs are proposed to leave the CNS via either (i) lymphatics of the cribriform plate, reaching the nasal mucosa lymphatic vasculature (particularly, dendritic cells may migrate along the rostral migratory stream [RMS] to enter the lymphatics via the olfactory bulb’s SAS); or (ii) the glymphatic pathway (as demonstrated for antigens), reaching the SAS and entering the meningeal lymphatic vasculature via SAS and trafficking to the dcLNs. APCs within the meningeal spaces may also leave through meningeal lymphatic vessels into the dcLNs. Each pathway’s contribution to cell and antigen drainage has yet to be determined.