The Meningeal Lymphatic System: A New Player in Neurophysiology

Abstract

Summary The nature of fluid dynamics within the brain parenchyma is a focus of intensive research. Of particular relevance is its participation in diseases associated with protein accumulation and aggregation in the brain, such as Alzheimer’s disease (AD). The meningeal lymphatic vessels of the central nervous system have recently been recognized as an important player in the complex circulation and exchange of soluble contents between the cerebrospinal fluid (CSF) and the interstitial fluid (ISF). In aging mammals, for example, impaired functioning of the meningeal lymphatic vessels can lead to accelerated accumulation of toxic amyloid beta protein in the brain parenchyma, thus aggravating AD-related pathology. Given that meningeal lymphatic vessels are functionally linked to paravascular influx/efflux of the CSF/ISF, and in light of recent findings that certain cytokines, classically perceived as immune molecules, exert neuromodulatory effects, it is reasonable to suggest that the activity of meningeal lymphatics could alter the accessibility of CSF-borne immune neuromodulators to the brain parenchyma, thereby altering their effects on the brain. Accordingly, in this Perspective we discuss the suggestion that the meningeal lymphatic system can be viewed as a novel player in neurophysiology.

Application of microscale culture technologies for studying lymphatic vessel biology

“…In addition, it was previously believed that the brain and CNS lacked a functional lymphatic system that could aid in immunosurveillance and fluid drainage . However, recent work has revealed that lymphatic vessels do in fact exist in the meninges of the brain . These findings have prompted a reassessment of the role of the lymphatic vasculature in the CNS and its involvement in a variety of neuroimmunological disorders.…”

“…165 However, recent work has revealed that lymphatic vessels do in fact exist in the meninges of the brain. [166][167][168] These findings have prompted a reassessment of the role of the lymphatic vasculature in the CNS and its involvement in a variety of neuroimmunological disorders. For instance, Kipnis and colleagues showed that meningeal lymphatic vessels play an essential role in draining amyloid-β peptides from cerebrospinal fluids and into cervical lymph node to maintain brain homeostasis.…”

Species differences in immune‐mediated CNS tissue injury and repair: A (neuro)inflammatory topic

“…Trafficking of immune constituents under physiologic conditions is more readily apparent between the systemic compartment and the meningeal compartment than between the former and the parenchymal compartment. The meningeal compartment also contains a lymphatic drainage system that allows for the trafficking of immune cells back to the systemic compartment(Da Mesquita, Fu, & Kipnis, 2018). These lymphatic channels can now be identified by magnetic resonance imaging (MRI) in humans(Absinta et al, 2017).Rua et al showed that in animals, recurrent infection in the meninges results in repopulation of this compartment with an expanded repertoire of myeloid cells(Rua et al, 2019).…”

The anatomy and metabolome of the lymphatic system in the brain in health and disease

“…In the glymphatic pathway, CSF flows into the brain along periarterial spaces and subsequently into the brain interstitium, carrying metabolic products from ISF; then, CSF flows toward the perivascular spaces (22,23,46,47,58). In the CSF drainage routes, CSF is transported mainly to meningeal lymphatic vessels or to perineural spaces across the cribriform plate leading to the nasal mucosa (4,13,27,29,39,41) and subsequently into cervical lymph nodes (3,38,42). These findings confirmed the presence of lymphatic vasculature in the brain, which serves as a draining route from brain ISF to peripheral lymph nodes.…”