Meningeal lymphatics: recent discovery defying the concept of central nervous system 'immune privilege'

By Jennifer Sokolowski, MD, PhD.

Identification and characterization of meningeal lymphatics

The recent discovery of a lymphatic system in the meninges surrounding the brain and spinal cord has spurred a surge of interest in and has redefined our understanding of immunity in the central nervous system (CNS).^1,2 The lymphatic system in the brain is composed of the glymphatic system and meningeal lymphatic vessels.³ The glymphatic system involves convective flow of cerebral spinal fluid and interstitial fluid and uses para-arterial flux to clear solutes and metabolites from the brain parenchyma. In concert, the meninges harbor bona fide lymphatic vessels and contribute to transport and drainage of immune cells, fluid, and small molecules from the brain to the CNS-draining lymph nodes.

Recent studies describe the development of meningeal lymphatics in mice. In the work by Anitla et al., they show that meningeal lymphatics in mice develop by postnatal day 21. As is true in the peripheral lymphatic system, meningeal lymphatics are localized adjacent to the vascular structures and seem to rely on signals from vascular smooth muscle cells, specifically VEGF-C, for proper development and maintenance. In this study, they use a host of markers to delineate meningeal lymphatics, including antibodies to Prox-1, LYVE-1, CCL21, and podoplanin, as well as Prox1-eGFP reporter mice.⁴

Immunocytochemistry/Immunofluorescence: PROX1 Antibody [NBP1-18605] - Frozen sections of a mouse embryo at day 13.5 with anti-CD31 [green] and anti-human Prox-1 [red]. It shows a large lymphatic vessel (lv), blood vessels (arrows) and a sympathetic ganglion (sg) which is also positive for Prox-1.

Studies in meninges from humans and non-human primates have also shown that lymphatic vessels lie adjacent vascular structures. Immunohistochemistry with antibodies to Prox1, LYVE-1, and podoplanin have shown that the lymphatic vessels parallel the venous sinuses.⁵

Markers of meningeal lymphatic cells

• Prox-1, prospero homeobox protein 1, is a homeobox transcription factor expressed in lymphatic endothelial cells (LECs) that is thought to be involved in gene transcriptional regulation and cell fate determination.⁶
• Lyve-1, lymphatic vessel endothelial hyaluronan receptor 1, also known as extracellular link domain containing 1, is a hyaluronan receptor expressed in LECs that is thought to play a role in hyaluronan clearance and hyaluronan-mediated leukocyte adhesion, although this is controversial.^6,7
• CCL21, chemokine-ligand 21, expressed and secreted by LECs, is thought to play an important role in transmigration of dendritic cells.⁸
• VEGF R3, vascular endothelial growth factor receptor 3, is a tyrosine kinase receptor that drives LEC development and maintenance through signaling from the ligand VEGF-C.⁴
• Podoplanin is an integral membrane glycoprotein which appears to play a role in lymphatic patterning and separation from blood vessels.⁶

Significance

Clearance of metabolites, antigens, and immune cells likely plays a critical role in CNS pathology in a variety of contexts, including cancers, infections, neurodegenerative diseases, and other injuries to the brain such as trauma and stroke. Studies characterizing the CNS lymphatic system may provide insight and ideas for new interventions and treatment options to treat CNS diseases.

Explore Lymphangiogenesis

Jennifer Sokolowski, MD, PhD
University of Virginia, Department of Neurosurgery
Jennifer is doing a postdoc while completing her residency in Neurosurgery and has background in basic science, specifically neuroscience, cell death, and immunology, as well as background in medicine and translational and clinical research.

References

1. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015 Jul 16;523(7560):337-41.
2. Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015 Jun 29;212(7):991-9.
3. Louveau A, Plog BA, Antila S, Alitalo K, Nedergaard M, Kipnis J.  Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J Clin Invest. 2017 Sep 1;127(9):3210-3219
4. Antila S, Karaman S, Nurmi H, Airavaara M, Voutilainen MH, Mathivet T, Chilov D, Li Z, Koppinen T, Park JH, Fang S, Aspelund A, Saarma M, Eichmann A, Thomas JL, Alitalo K. Development and plasticity of meningeal lymphatic vessels.  J Exp Med. 2017 Dec 4;214(12):3645-3667.
5. Absinta M, Ha SK, Nair G, Sati P, Luciano NJ, Palisoc M, Louveau A, Zaghloul KA, Pittaluga S, Kipnis J, Reich DS. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. Elife. 2017 Oct 3;6.
6. Jha SK, Rauniyar K, Jeltsch M. Key molecules in lymphatic development, function, and identification. Ann Anat. 2018 May 26;219:25-34.
7. Johnson LA, Prevo R, Clasper S, Jackson DG. Inflammation-induced uptake and degradation of the lymphatic endothelial hyaluronan receptor LYVE-1. J Biol Chem. 2007 Nov 16;282(46):33671-80.
8. Johnson LA, Jackson DG. Inflammation-induced secretion of CCL21 in lymphatic endothelium is a key regulator of integrin-mediated dendritic cell transmigration. Int Immunol. 2010 Oct;22(10):839-49