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.

Figure 1. 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.

Figure 2. Glymphatic and lymphatic drainage pathways from the CNS to the cervical lymph nodes.

(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.

Figure 3. Potential modulation of T cell activation by lymphatic ECs.

Lymphatic ECs (LECs) (primarily within the lymph nodes) can modulate T cell activation directly, either by producing modulatory molecules (NO, IDO, TGF-β) or by expressing MHC and costimulatory molecules like PDL1. Alternatively, the regulation can also be indirect by inducing maturation of dendritic cells (DCs) via ICAM-1 expression. Moreover, soluble molecules draining from the CSF to the dcLNs are taken up by subcapsular APCs (DCs and macrophages), resulting in modulation of B and T cell activation in the dcLNs. This function of meningeal lymphatic vessels in regulation of meningeal T cell tolerance has not yet been explored. IDO, Indoleamine 2,3-dioxygenase; PD1, programmed death 1; PDL1, Programmed death ligand 1.