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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Category: Review Series

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 1

Circulation of CSF, ISF, and brain solute through the glymphatic pathway.

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Circulation of CSF, ISF, and brain solute through the glymphatic pathway...
(A) CSF within the subarachnoid and cisternal spaces flows into brain specifically via periarterial spaces and then exchanges with ISF facilitated by aquaporin-4 (AQP4) water channels that are positioned within perivascular astrocyte end-foot processes. The bulk movement of CSF into brain drives the convective flow of ISF and interstitial solute through the extracellular space to ultimately collect within perivenous spaces. (B) Perivenous fluid and solute then drain from brain predominantly alongside large-caliber ventral veins. Once within the subarachnoid CSF, solutes such as amyloid-β can exit the cranium via arachnoid granulations or meningeal lymphatic vessels or along cranial and spinal nerves; however, a proportion is also capable of recirculating into brain via periarterial spaces. Periarterial solute may seed and accumulate within the basement membranes of smooth muscle cells, precipitating conditions such as cerebral amyloid angiopathy.