Meningeal lymphatic vessels

The meningeal lymphatic vessels (or meningeal lymphatics) are a network of conventional lymphatic vessels located parallel to the dural venous sinuses and middle meningeal arteries 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 into the deep cervical lymph nodes. Cerebrospinal fluid and interstitial fluid are exchanged, and drained by the meningeal lymphatic vessels. While it was historically believed that both the brain and meninges were devoid of lymphatic vasculature, recent studies by Antoine Louveau and Jonathan Kipnis at the University of Virginia, submitted in October 2014, and by Aleksanteri Aspelund, Salli Antila and Kari Alitalo at the University of Helsinki submitted in December 2014, identified and described the basic biology of the meningeal lymphatics using a combination of histological, live-imaging, and genetic tools. 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. The role that the meningeal lymphatics plays in neurological disease is yet to be explored. It is hypothesized 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. The first mention of meningeal lymphatic vessels can be attributed to Paolo Mascagni, whose anatomical work towards the end of the eighteenth century suggested their presence; however, this work received little attention or acceptance. In 1953, Italian scientist Lecco identified putative lymphatic vessels in post-mortem human dura. Further research in the 1960s described the existence of meningeal lymphatics, but these findings were not accepted by the field due to their limited methodology. Prior to the discovery of true meningeal lymphatic vessels, it was generally believed that the mammalian CNS did not contain a lymphatic system and thus relied upon alternative routes of waste clearance such as the glymphatic system, a cerebrospinal fluid (CSF) drainage pathway under the cribriform plate and into the lymphatics of the nasal mucosa, 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 highly restricted access under normal physiological conditions.

Discovery Although several studies proposed the existence of lymphatic vessels in the dura mater, the presence of the meningeal lymphatic system was accepted in 2015, when two independent studies published by Louveau et al. and Aspelund et al. provided convincing data using novel methods. Louveau et al. noticed an unusual alignment of immune cells along the dural sinus using a meningeal whole-mount technique. Using lymphatic endothelial cell-specific markers and electron microscopy, the authors found that the immune cells were not inside blood vessels, but rather were organized inside lymphatic vessels within the meninges, a system of membranes that envelop the brain and spinal cord. Aspelund et al. had discovered that in the eye, another immune-privileged organ, the Schlemm's canal is a lymphatic-like vessel. Building upon this insight, the authors hypothesized that similar vessels might exist in the meninges, given its immune-privileged status, eventually leading to the identification of meningeal lymphatic 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. While many scientists study the brain parenchyma proper, Kipnis explained, his lab is relatively unique in studying the meninges:

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.

Visualization

To visualize the dura mater using immunohistochemistry, the dura must first be fixed within the skullcap. It is prepared by cutting around the base of the skull (inferior to the post-tympanic hook) and removing the lower portion of the skull and brain. Following fixation, the dura can be dissected out of the skullcap as a single piece of tissue that can be utilized for histological analysis. In transgenic mice containing Prox1-GFP or Vegfr3-LacZ reporter genes, the lymphatic vessels may be visualized by fluorescent microscopy or after X-gal staining, respectively. The meningeal lymphatics may also be visualized non-invasively by MRI, using MRI contrast agents such as gadobutrol and gadofosveset to reveal the presence of the vessels near the dura mater.

Biology

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