Unraveling the link between brain and lymphatic system

Researchers at the University of Helsinki and Wihuri Research Institute report an exceptionally surprising finding that argues against all previous anatomy and histology textbook knowledge – lymphatic vessels exist in the central nervous system.

The authors’ original image shows two dura mater lymphatic vessels (red) running along meningeal blood vessels (green).Researcher Aleksanteri Aspelund and colleagues discovered a lymphatic vessel network in the mouse meningeal linings and that these vessels have a direct connection to the body’s systemic lymphatic network.

Lymphatic circulation forms a network that covers almost the whole body and is especially important to the tissue clearance of excess fluid and macromolecules as well as to the immune defense mechanisms. Until now, the central nervous system has been considered an immune-privileged organ not connected to the lymphatic system.

– We have recently discovered that in the eye, which is another immune-privileged organ previously considered to lack lymphatic circulation, there exists a lymphatic-like vessel. This lead us to investigate the lymphatic nature of the brain in more detail, says Aspelund, who has been working in Academy Professor Kari Alitalo’s research group.

– However, we didn’t expect to find such an extensive network directly connected to the brain.  This incredible finding completely changes our understanding of the brain anatomy and gives a chance to look at brain diseases from a completely new angle, he continues.

The researchers have done an excellent job in characterizing the structure and function of these previously unknown vessels. They show that these meningeal lymphatic vessels drain out of the skull via the foramina of the base of the skull alongside arteries, veins and cranial nerves.

These vessels show all molecular hallmarks of the lymphatic vessels and function as a direct clearance routes for the brain and cerebrospinal fluid macromolecules out of the skull and into the deep cervical lymph nodes.

How the lymphatic vessels managed to escape notice all this time?

– This is no wonder, says medical student Salli Antila, who has also been working with the project.

– Lymphatic vessels are so closely attached to the structures inside the meninges that if you don’t know what you’re looking for, you will probably miss them. Although we had already found the vessels, it took some time to develop good imaging methods to visualize the vessels, especially for the structures at the bottom of the skull.

The discovery has raised several new questions concerning fundamental brain functions and the mechanisms of brain diseases.

Researchers find it highly possible that lymphatic clearance of the brain might prove to be extremely important in neuro-immunological diseases as well as in diseases characterized by the pathological accumulation of misfolded proteins or fluid into the brain parenchyma, such as Alzheimer’s disease, which affects tens of millions of people worldwide.

The findings have been published online by Journal of Experimental Medicine.

(Click to enlarge) A schematic image of the novel lymphatic vessel network in the meningeal linings of the brain, discovered by Aleksanteri Aspelund and collaborators. (A) Previously, lymphatic vessels in the nasal mucosa were known to drain cerebrospinal fluid, but it was thoughts that the lymphatic vessels did not extend into the brain. (B-C) The new findings revealed that the dura mater lymphatic system is important for the drainage of brain interstitial fluid, macromolecules and cerebrospinal fluid.

Text: Päivi Lehtinen
Figures: Alitalo Lab

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Wihuri Research Institute

Biomedicum Helsinki
Haartmaninkatu 8
FI-00290 HELSINKI
Finland
Director: Kari Alitalo
 
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