The Cerebral Lymphatic System: Function, Controversies, and Therapeutic Approaches for Central Nervous System Diseases.

Abstract

The meninges serve as critical barriers that maintain immune homeostasis in the central nervous system (CNS) and play vital roles in immune surveillance and defense. Traditionally, the brain has been regarded as an "immune-privileged" organ owing to the absence of conventional lymphatic vessels. However, the rediscovery of meningeal lymphatic vessels (MLVs) has revealed a mechanism for the directional transport of cerebrospinal fluid (CSF) to the deep cervical lymph nodes (dCLNs), demonstrating that the brain possesses a distinct fluid communication pathway with the peripheral system that is independent of blood circulation. Additionally, the identification of the glymphatic system has revealed a perivascular mechanism for solute exchange between the CSF and brain parenchyma, primarily mediated by the astrocytic water channel protein aquaporin-4 (AQP4). These discoveries have significantly expanded our understanding of brain fluid dynamics and CNS homeostasis. This review provides a comprehensive overview of the structure, regulation, and function of MLVs and the glymphatic system, which together constitute lymphatic system of the brain. We also discuss recent evidence, particularly conflicting perspectives, on the role of meningeal immunity in various central nervous system (CNS) disorders, such as multiple sclerosis, Parkinson's disease, and epilepsy. Furthermore, we explore the therapeutic potential of targeting the brain lymphatic system to treat these conditions. Given their critical roles in CNS homeostasis, MLVs and the glymphatic system have emerged as promising therapeutic targets, potentially offering novel treatment strategies for currently incurable neurological diseases.