Meningeal lymphatic vessels: Difference between revisions
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The meningeal lymphatics are a recently discovered network of classical lymphatic vessels located parallel to the dural sinus of the mammalian central nervous system (CNS). As a part of the lymphatic system, the meningeal lymphatics are responsible for draining immune cells, small molecules, and excess fluid from the CNS and into the deep cervical lymph nodes.[1]
While it was initially believed that both the brain and meninges were devoid of lymphatic vasculature, recent studies led by neuroimmunologists Antoine Louveau and Jonathan Kipnis at the University of Virginia identified and described the basic biology of the meningeal lymphatics using a combination of histological, live-imaging, and genetic tools.[1] In general, their work is thought to extend that of the Danish neuroscientist Maiken Nedergaard in identifying the pathway connecting the glymphatic system to the meningeal compartment.
Currently, the role that the meningeal lymphatics play in neurological disease is yet to be explored. However, there is some speculation that they may contribute to autoimmune and inflammatory diseases of the CNS due to their role in connecting the immune and nervous systems.
Background
In peripheral organs, lymphatic vessels are responsible for conducting lymph between different parts of the body. In general, lymphatic drainage is important for maintaining fluid homeostasis as well as providing a means for immune cells to traffic into draining lymph nodes from other parts of the body, allowing for immune surveillance of bodily tissues.
For years, it was thought that the mammalian CNS did not contain a lymphatic system and thus relied upon alternative routes such as the glymphatic system[2], a CSF drainage pathway under the cribriform plate and into the lymphatics of the nasal mucosa,[3] and arachnoid granulations to clear itself of excess protein, fluid, and metabolic waste products. Furthermore, the presumed absence of CNS lymphatics was an important pillar in the long-held dogma that the CNS is an immune-privileged tissue to which immune cells have incredibly restricted access under normal physiological conditions.
Hidden vessels
In an interview with Ira Flatow on NPR’s Science Friday, Kipnis described the meningeal lymphatics as “well-hidden” when asked how, unlike the rest of the lymphatic system, they had remained unmapped into the 21st century[4]. While many scientists study the brain parenchyma proper, Kipnis explained, his lab is relatively unique in studying the meninges, a system of membranes that envelop the brain and spinal cord.
“We are among the few labs who are interested in this very unique area of the brain: the coverings of the brain - the so-called ‘meninges.’ We’ve been looking into this area for a few years now,” Kipnis said. “I was lucky to have a phenomenal post-doctoral fellow in my lab, Dr. Antoine Louveau, who developed a very unique technique of mounting this entire covering as a whole-mount. I think this is what allowed us to find those vessels.”[4]
Meningeal whole-mount technique
To visualize the dura using immunohistochemistry, Louveau et al. developed a novel method of dissecting, preparing, and staining meningeal tissue from adult mice as a whole-mount.[5]
Briefly, the technique entails cutting around the base of the skull (inferior to the post-tympanic hook), removing the lower portion of the skull and brain, and fixing the dura within the skullcap. Following fixation, the dura can be dissected out of the skullcap as a single piece of tissue that can be utilized for histological analysis.[5]
Basic biology of the meningeal lymphatics
Anatomy and route of drainage
After noticing an unusual alignment of immune cells along the dural sinus using the meningeal whole-mount technique, Louveau et al. found a network of vessels in the dura that expressed lymphatic endothelial cell marker proteins, including PROX1, LYVE1, and PDPN.[1]. In follow-up experiments, the vessels were also shown to be located exterior to the sinusal lumen, to extend along the length of both the superior sagittal and transverse sinuses, and (after the performance of anatomical tracing experiments with Evans blue dye) to directly connect to the deep cervical lymph nodes.[1]
Importantly, the meningeal lymphatics present several unique attributes that differentiate them from lymphatic vessels in peripheral organs. Compared to peripheral lymphatic vessels, the meningeal lymphatic network is markedly less complex (with far less tissue coverage and lymphatic branching). Furthermore, meningeal lymphatic vessels are generally smaller than those in the periphery and display an interesting structural homogeneity along the dural sinuses, remaining thinner and mostly unbranched along the superior sagittal sinus while growing larger and more branched along the transverse sinuses.[1]
Physiological roles in draining CSF and immune cells
Like peripheral lymphatic vessels, the meningeal lymphatics were shown to serve both the tissue drainage and immune cell trafficking functions of the lymphatic system. First, multiphoton live imaging experiments performed on anesthetized mice demonstrated that the meningeal lymphatics are capable of draining fluorescent dyes injected intracisternally into the CSF, indicating that the meningeal lymphatics are capable of draining fluid from their surrounding environment. In addition, histological analysis revealed that the meningeal lymphatics constitutively contain T cells, B cells, and MHC class II-expressing myeloid cells, demonstrating that meningeal lymphatic vessels are capable of carrying immune cells.[1]
Additional studies also showed that the meningeal lymphatics respond to recombinant vascular endothelial growth factor (VEGF) exposure by increasing in diameter, providing evidence that the meningeal lymphatics share developmental characteristics with those in the periphery.[1]
Implications for neurological disease
The role, if any, that the meningeal lymphatics play in diseases of the nervous system is an area of active research - particularly with regard to neurological disorders in which immunity is a fundamental player such as multiple sclerosis, Alzheimer’s Disease, amyotrophic lateral sclerosis, Hennekam syndrome, and Prader-Willi syndrome. Importantly, however, Louveau et al. demonstrated that there seem to be identifiable meningeal lymphatic vessels in post-mortem human tissue, suggesting the possibility that they contribute to human disease.
Further reading
Since the work of Louveau et al., the anatomy and basic biology of the meningeal lymphatics have been independently confirmed by Aspelund et al. in a study published in the Journal of Experimental Medicine [6].
Furthermore, work characterizing the meningeal lymphatics has been covered in a variety of news outlets, including Time Magazine,[7] The Guardian,[8], The Huffington Post,[9] NPR,[4] and several science blogs.[10]
References
- ^ a b c d e f g "Structural and functional features of central nervous system lymphatic vessels". Nature. 2015. doi:10.1038/nature14432. PMID 26030524.
{{cite journal}}: Cite uses deprecated parameter|authors=(help) - ^ Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M (2012). "A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β". Sci Trans Med. 4 (147): 147ra111. doi:10.1126/scitranslmed.3003748. PMC 3551275. PMID 22896675.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Cserr HF, Harling-Berg CJ, Knopf PM (1992). "Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance". Brain Pathol. 4 (147): 147ra111. PMID 1341962.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ a b c Lim, Alexa (5 June 2015). "A potential "missing link" between the brain and immune system". National Public Radio. Retrieved 24 June 2015.
{{cite web}}: Italic or bold markup not allowed in:|publisher=(help) - ^ a b c "Dissection and immunostaining of mouse whole-mount meninges". Protocol Exchange. 2015. doi:10.1038/protex.2015.047.
{{cite journal}}: Cite uses deprecated parameter|authors=(help) - ^ "A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules". Journal of Experimental Medicine. 2015. doi:10.1084/jem.20142290. PMID 26077718.
{{cite journal}}: Cite uses deprecated parameter|authors=(help); Italic or bold markup not allowed in:|journal=(help) - ^ Greenberg, Alissa (3 June 2015). "Game-changing discovery links the brain and the immune system". Time. Retrieved 24 June 2015.
{{cite web}}: Italic or bold markup not allowed in:|publisher=(help) - ^ Devlin, Hannah (5 June 2015). "Newly discovered vessels beneath skull could link brain and immune system". The Guardian. Retrieved 24 June 2015.
{{cite web}}: Italic or bold markup not allowed in:|publisher=(help) - ^ Gregoire, Carolyn (5 June 2015). "Landmark study finds previously unknown link between the brain and immune system". Huffington Post. Retrieved 24 June 2015.
{{cite web}}: Italic or bold markup not allowed in:|publisher=(help) - ^ Taylor, Ashley (1 June 2015). "Brain Drain". The Scientist. Retrieved 24 June 2015.
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