Nasopharyngeal lymphatic plexus is a hub for cerebrospinal fluid drainage

Abstract

Cerebrospinal fluid (CSF) in the subarachnoid space around the brain has long been known to drain through the lymphatics to cervical lymph nodes1–17, but the connections and regulation have been challenging to identify. Here, using fluorescent CSF tracers in Prox1-GFP lymphatic reporter mice18, we found that the nasopharyngeal lymphatic plexus is a major hub for CSF outflow to deep cervical lymph nodes. This plexus had unusual valves and short lymphangions but no smooth-muscle coverage, whereas downstream deep cervical lymphatics had typical semilunar valves, long lymphangions and smooth muscle coverage that transported CSF to the deep cervical lymph nodes. α-Adrenergic and nitric oxide signalling in the smooth muscle cells regulated CSF drainage through the transport properties of deep cervical lymphatics. During ageing, the nasopharyngeal lymphatic plexus atrophied, but deep cervical lymphatics were not similarly altered, and CSF outflow could still be increased by adrenergic or nitric oxide signalling. Single-cell analysis of gene expression in lymphatic endothelial cells of the nasopharyngeal plexus of aged mice revealed increased type I interferon signalling and other inflammatory cytokines. The importance of evidence for the nasopharyngeal lymphatic plexus functioning as a CSF outflow hub is highlighted by its regression during ageing. Yet, the ageing-resistant pharmacological activation of deep cervical lymphatic transport towards lymph nodes can still increase CSF outflow, offering an approach for augmenting CSF clearance in age-related neurological conditions in which greater efflux would be beneficial.

Emergence of the brain-border immune niches and their contribution to the development of neurodegenerative diseases

“…The lymphatic system also functions as an active immune surveillance system, with downstream lymph nodes housing germinal centres for pathogen recognition, and endothelial cells that secrete specific cytokines and express membrane adhesive factors for leukocytic diapedesis into the surrounding tissues ( 84 ). Although the CNS does not possess perforating lymphatics, recent advancements in high-resolution imaging techniques have revealed the presence of lymphatic channels coursing in a specific manner within the dura mater of transgenic Prox1-EGFP-expressing mice stained for LYVE1 ( 85 ). Additionally, leptomeningeal lymphatic endothelial cells (LLECs) have been suggested to reside in non-lumenised lymphatic endothelium within the leptomeninges ( 86 ).…”

“…CSF from the brain parenchyma is generally known to flow through one of two different lymphatic routes. At the caudal end of the brain, CSF is drained from the sigmoid sinus through basolateral lymphatics at the dura, passing through the jugular foramen to lateral deep lymphatics, before directly arriving at the lateral cervical lymph nodes ( 85 ). In contrast, at the rostral parts of the brain, particularly the cavernous sinus and olfactory bulb, lymphatics pass through the cribriform plate to the olfactory epithelium adjacent to the olfactory neurons ( 87 ).…”

“…A recent study has shown that, in both mice and macaques, the olfactory lymphatics link posteriorly to a lymphatic plexus superior to the nasopharynx bone at the skull base ( 85 ). This plexus structure, termed the nasopharyngeal lymphatic plexus (NPLP), subsequently merges with the medial cervical lymphatics, which ultimately connect to the deep cervical lymph nodes ( 85 ).…”

“…A recent study has shown that, in both mice and macaques, the olfactory lymphatics link posteriorly to a lymphatic plexus superior to the nasopharynx bone at the skull base ( 85 ). This plexus structure, termed the nasopharyngeal lymphatic plexus (NPLP), subsequently merges with the medial cervical lymphatics, which ultimately connect to the deep cervical lymph nodes ( 85 ). Structurally, the plexus consists of a flattened network of unicellular capillaries characterised by button-like and zipper-like junctions, numerous unique valves, as well as the absence of a smooth muscle layer ( 85 ).…”

“…This plexus structure, termed the nasopharyngeal lymphatic plexus (NPLP), subsequently merges with the medial cervical lymphatics, which ultimately connect to the deep cervical lymph nodes ( 85 ). Structurally, the plexus consists of a flattened network of unicellular capillaries characterised by button-like and zipper-like junctions, numerous unique valves, as well as the absence of a smooth muscle layer ( 85 ). These unique histological features allow the NPLP to be classified as a form of precollecting lymphatics, with extensive valvular structures to ensure the unidirectional flow of CSF towards the deep cervical lymph nodes.…”