Glymphatic and lymphatic communication with systemic responses during physiological and pathological conditions in the central nervous system

Abstract

Crosstalk between central nervous system (CNS) and systemic responses is important in many pathological conditions, including stroke, neurodegeneration, schizophrenia, epilepsy, etc. Accumulating evidence suggest that signals for central-systemic crosstalk may utilize glymphatic and lymphatic pathways. The glymphatic system is functionally connected to the meningeal lymphatic system, and together these pathways may be involved in the distribution of soluble proteins and clearance of metabolites and waste products from the CNS. Lymphatic vessels in the dura and meninges transport cerebrospinal fluid, in part collected from the glymphatic system, to the cervical lymph nodes, where solutes coming from the brain (i.e., VEGFC, oligomeric α-syn, β-amyloid) might activate a systemic inflammatory response. There is also an element of time since the immune system is strongly regulated by circadian rhythms, and both glymphatic and lymphatic dynamics have been shown to change during the day and night. Understanding the mechanisms regulating the brain-cervical lymph node (CLN) signaling and how it might be affected by diurnal or circadian rhythms is fundamental to find specific targets and timing for therapeutic interventions.

Fig. 1. CSF outflow pathways.

1 CSF flows through arachnoid villi, found along the superior sagittal venous sinus, into the blood 2 It drains through the cribriform plate in association with the olfactory nerves. From this location, CSF is absorbed into nasal mucosal lymphatics. It does eventually reach the CLNs 3 It flows from the meningeal lymphatics directly to cervical lymph nodes 4 CSF transits into the skull marrow trough skull channels.

Fig. 2. Glymphatic system and meningeal lymphatic system.

The glymphatic system drains CSF into the brain via a periarterial pathway, while interstitial fluid (ISF) leaves the brain through the perivenous pathway. CSF, containing macromolecules and immune cells, can flow from the brain parenchyma through the dura meningeal lymphatics into the lymph nodes and extracranial systemic circulation. In some pathological conditions 1 Altered expression of polarized AQP4 prevents CSF/ISF exchange by reducing the interstitial space volume, reducing the waste clearance 2 The meningeal lymphatic vessels transport CSF, containing solutes coming from the brain (such as VEGFC, oligomeric α-syn, β-amyloid) into the cervical lymph nodes, activating inflammatory response.