Mar 25, 2018 - He believed lymphatic drainage from the brain was occurring but he didn't know from where. Phil Hayward on March 29, 2018 at 3:08 am.

The central nervous system (CNS) is considered an organ devoid of lymphatic vasculature. Yet, part of the cerebrospinal fluid (CSF) drains into the cervical lymph nodes (LNs).

The mechanism of CSF entry into the LNs has been unclear. Here we report the surprising finding of a lymphatic vessel network in the dura mater of the mouse brain. We show that dural lymphatic vessels absorb CSF from the adjacent subarachnoid space and brain interstitial fluid (ISF) via the glymphatic system. Dural lymphatic vessels transport fluid into deep cervical LNs (dcLNs) via foramina at the base of the skull. In a transgenic mouse model expressing a VEGF-C/D trap and displaying complete aplasia of the dural lymphatic vessels, macromolecule clearance from the brain was attenuated and transport from the subarachnoid space into dcLNs was abrogated. Surprisingly, brain ISF pressure and water content were unaffected.

Overall, these findings indicate that the mechanism of CSF flow into the dcLNs is directly via an adjacent dural lymphatic network, which may be important for the clearance of macromolecules from the brain. Importantly, these results call for a reexamination of the role of the lymphatic system in CNS physiology and disease. Lymphatic circulation extends throughout most of the body and contributes to tissue homeostasis and function by facilitating the clearance of excess fluid and macromolecules from the interstitium (). However, the central nervous system (CNS) is considered to lack lymphatic vasculature, which has raised long-standing questions about how cerebral interstitial fluid (ISF) is cleared of waste products (). The exchange of compounds is limited by the blood–brain barrier, which functions as a diffusion barrier between the brain and circulating blood. Therefore, the transvascular clearance of most compounds is dependent on specific active transporter mechanisms (). In addition, the brain has adapted to use a unique paravascular route in which fluids may freely exchange between the brain ISF and the cerebrospinal fluid (CSF) along glial “lymphatic” (glymphatic) routes without crossing the tightly regulated endothelial cell (EC) layer (; ).

Downstream of the glymphatic system, the majority of the CSF is considered to drain into the venous circulation through arachnoid granulations. Still, several studies have found that a substantial proportion of the CSF is also drained into extracranial lymphatic vessels and LNs (). However, the mechanisms of CSF entry into the extracranial lymphatic compartment are unclear. Lymphatic vessels in the dura mater surrounding the brain The brain is enveloped by meningeal linings consisting of three layers: the pia mater tightly attached to the surface of the brain, the avascular arachnoid mater overlying the subarachnoid space, and the vascularized dura mater fused to the cranial bones. To determine whether lymphatic vessels exist within the CNS and surrounding meninges, we analyzed the Prox1-GFP and Vegfr3 +/LacZ reporter mice and whole-mount immunofluorescence preparations of the skull and brain of WT mice against LYVE1, PROX1, PDPN, CCL21, VEGFR3, and PECAM1. To visualize blood vessels, the Prox1-GFP mice were perfused with the fluorescent dye 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine (DiI; ).