CNS-Draining Meningeal Lymphatic Vasculature: Roles, Conundrums and Future Challenges

Abstract

A genuine and functional lymphatic vascular system is found in the meninges that sheath the central nervous system (CNS). This unexpected (re)discovery led to a reevaluation of CNS fluid and solute drainage mechanisms, neuroimmune interactions and the involvement of meningeal lymphatics in the initiation and progression of neurological disorders. In this manuscript, we provide an overview of the development, morphology and unique functional features of meningeal lymphatics. An outline of the different factors that affect meningeal lymphatic function, such as growth factor signaling and aging, and their impact on the continuous drainage of brain-derived molecules and meningeal immune cells into the cervical lymph nodes is also provided. We also highlight the most recent discoveries about the roles of the CNS-draining lymphatic vasculature in different pathologies that have a strong neuroinflammatory component, including brain trauma, tumors, and aging-associated neurodegenerative diseases like Alzheimer's and Parkinson's. Lastly, we provide a critical appraisal of the conundrums, challenges and exciting questions involving the meningeal lymphatic system that ought to be investigated in years to come.

Keywords: aging; central nervous system; cerebrospinal fluid; disease; drainage; lymphatic vessels; meninges; neuroinflammation.

FIGURE 1

Scheme depicting the structure of meningeal lymphatic vessels, lymphatic drainage of CSF solutes/molecules, mechanisms regulating the trafficking of immune cells through meningeal lymphatics and the unidirectional lymphatic flow into the brain draining CLNs. CCL19/21, C–C motif chemokine ligand 19/21; CCR7, C–C motif chemokine receptor 7; COS, confluence of sinuses; CSF, cerebrospinal fluid; LECs, lymphatic endothelial cells; LYVE-1, lymphatic vessel endothelial hyaluronan receptor-1; MMA, middle meningeal artery; PSS, petrosquamosal sinus; RRV, rostral rhinal vein; S1P, sphingosine-1-phosphate; S1PRs, sphingosine-1-phosphate receptors; SMCs, smooth muscle cells; SS, sigmoid sinus; SSS, superior sagittal sinus; TS, transverse sinus. Created with BioRender.com.

FIGURE 2

Effects of meningeal lymphatic (dys)function on CSF drainage, immune cell trafficking into the cervical lymph nodes, meningeal immunity, CNS immune surveillance, neuroinflammation and other neural processes, either under physiological conditions or in disease models. Aβ, amyloid beta; AD, Alzheimer’s disease; CNS, central nervous system; CSF, cerebrospinal fluid; CLNs, cervical lymph nodes; ISF, interstitial fluid; LVs, lymphatic vessels; PD, Parkinson’s disease. Created with BioRender.com.