The Glymphatic System and Meningeal Lymphatics: Current Understandings and Future Perspectives

Abstract

The central nervous system (CNS) maintains homeostasis and immune surveillance through a recently defined brain-wide clearance network: the glymphatic–lymphatic axis. This system couples the intramural glymphatic pathway, responsible for convective fluid transport and parenchymal waste removal, with the meningeal lymphatic vessels (MLVs), which serve as the critical efferent route to the peripheral immune system. This review delineates the structural and functional foundations of each component, their regulatory dynamics, including the roles of sleep and aging, and their synergistic interplay in maintaining fluid balance, clearing metabolic waste, and facilitating neuroimmune communication. Mounting evidence identifies the dysfunction of this integrated axis as a common pathological mechanism across a spectrum of neurological disorders. We highlight its pivotal role in three key paradigms: acute injury (stroke), chronic proteinopathy (Alzheimer's disease, AD), and autoimmune dysregulation (multiple sclerosis, MS), where impaired clearance and maladaptive immune responses are central, recurring themes. The review critically evaluates emerging translational strategies aimed at therapeutically modulating this axis, including pharmacological targets (VEGF-C, Piezo1 agonists), noninvasive neuromodulation (photo-biomodulation, PBM), and surgical interventions (lymphaticovenous anastomosis, LVA). This synthesis positions the glymphatic–lymphatic axis as a fundamental physiological network and a pivotal target for novel interventions, outlining key future research directions in neurology.

Keywords

central nervous system / glymphatic system / meningeal lymphatics / neuroinflammation

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