Structural and functional features of central nervous system lymphatic vessels (original) (raw)
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Structural and functional features of central nervous system lymphatics
-privileged organ, largely because of the lack of classical lymphatic drainage system. However, immune surveillance of the CNS and the presence of meningeal T cells are now well established, although the mechanisms governing immune-cell circulation through the CNS have remained poorly understood. Here we report that in searching for T-cell gateways into and out of the brain meninges, we discovered conduits for immune cells in vessel-like structures immediately adjacent to the dural sinuses. These structures expressed the endothelial cell marker CD31, and exhibited all of the molecular hallmarks of lymphatic endothelial cells. Using intravital multiphoton microscopy we demonstrated that meningeal lymphatic vessels drain cerebrospinal fluid (CSF) and immune cells from meningeal spaces and that their obstruction results in a significant increase in the numbers of meningeal T cells. The unique location of these meningeal lymphatic vessels adjacent to the dural sinuses may have impeded their discovery up to now, thereby contributing to the long-held concept that the immune privilege of the brain is attributable to the absence of lymphatic vessels. This discovery of lymphatic drainage of immune cells and molecules from the meninges via bona-fide lymphatic vessels calls for a reassessment of basic assumptions in neuroimmunology and may shed new light on the etiology of neuroinflammatory and neurodegenerative diseases associated with immune-system dysfunction.
Conserved meningeal lymphatic drainage circuits in mice and humans
Journal of Experimental Medicine
Meningeal lymphatic vessels (MLVs) were identified in the dorsal and caudobasal regions of the dura mater, where they ensure waste product elimination and immune surveillance of brain tissues. Whether MLVs exist in the anterior part of the murine and human skull and how they connect with the glymphatic system and extracranial lymphatics remained unclear. Here, we used light-sheet fluorescence microscopy (LSFM) imaging of mouse whole-head preparations after OVA-A555 tracer injection into the cerebrospinal fluid (CSF) and performed real-time vessel-wall (VW) magnetic resonance imaging (VW-MRI) after systemic injection of gadobutrol in patients with neurological pathologies. We observed a conserved three-dimensional anatomy of MLVs in mice and humans that aligned with dural venous sinuses but not with nasal CSF outflow, and we discovered an extended anterior MLV network around the cavernous sinus, with exit routes through the foramina of emissary veins. VW-MRI may provide a diagnostic ...
CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature
Nature neuroscience, 2018
Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfill two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lym...
A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules
The Journal of experimental medicine, 2015
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 ...
Background: Studies in rodents have rekindled interest in the study of lymphatics in the central nervous system. Animal studies have demonstrated that there is a connection between the subarachnoid space and deep cervical lymph nodes (DCLNs) through dural lymphatic vessels located in the skull base and the parasagittal area. Objective: To describe the connection of the DCLNs and lymphatic tributaries with the intracranial space through the jugular foramen, and to address the anatomical features and variations of the DCLNs and associated lymphatic channels in the neck. Methods: Twelve formalin-fixed human head and neck specimens were studied. Samples from the dura of the wall of the jugular foramen were obtained from two fresh human cadavers during rapid autopsy. The samples were immunostained with podoplanin and CD45 to highlight lymphatic channels and immune cells, respectively. Results: The mean number of nodes for DCLNs was 6.91 ± 0.58 on both sides. The mean node length was 10.1 ± 5.13 mm, the mean width was 7.03 ± 1.9 mm, and the mean thickness was 4 ± 1.04 mm. Immunohistochemical staining from rapid autopsy samples demonstrated that lymphatic vessels pass from the intracranial compartment into the neck through the meninges at the jugular foramen, through tributaries that can be called intrajugular lymphatic vessels. Conclusions: The anatomical features of the DCLNs and their connections with intracranial lymphatic structures through the jugular foramen represent an important possible route for the spread of cancers to and from the central nervous system; therefore, it is essential to have an in-depth understanding of the anatomy of these lymphatic structures and their variations.
Frontiers in Physiology
The contribution of cranial dura mater vascular networks, as means for maintaining brain fluid movement and balance, and as the source of significant initiators and/or contributors to neurological disorders, has been overlooked. These networks consist of both blood and lymphatic vessels. The latter were discovered recently and described as sinus-associated structures thus changing the old paradigm that central nervous system lacks lymphatics. In this study, using markers specific to blood and lymphatic endothelia, we demonstrate the existence of the complex non-sinus-associated pachymeningeal lymphatic vasculature. We further show the interrelationship and possible connections between lymphatic vessels and the dural blood circulatory system. Our novel findings reveal the presence of lymphatic-like structures that exist on their own and/or in close proximity to microvessels. Of particular interest are subsets of vascular complexes with dual (lymphatic and blood) vessel identity representing a unique microenvironment within the cranial dura. The close association of the systemic blood circulation and meningeal lymphatics achieved in these complexes could facilitate fluid exchange between the two compartments and constitute an alternative route for CSF drainage.
Pathophysiology, 2010
In most organs of the body, immunological reactions involve the drainage of antigens and antigen presenting cells (APCs) along defined lymphatic channels to regional lymph nodes. The CNS is considered to be an immunologically privileged organ with no conventional lymphatics. However, immunological reactions do occur in the CNS in response to infections and in immune-mediated disorders such as multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Here, we review evidence that cervical lymph nodes play a role in B and T cell mediated immune reactions in the CNS. Then we define the separate pathways by which interstitial fluid (ISF) and CSF drain to cervical lymph nodes. ISF and solutes drain from the brain along the 100-150 nm-wide basement membranes in the walls of capillaries and arteries. In humans, this perivascular pathway is outlined by the deposition of insoluble amyloid (A) in capillary and artery walls in cerebral amyloid angiopathy in Alzheimer's disease. The failure of APCs to migrate to lymph nodes along perivascular lymphatic drainage pathways may be a major factor in immunological privilege of the brain. Lymphatic drainage of CSF is predominantly through the cribriform plate into nasal lymphatics. Lymphatic drainage of ISF and CSF and the specialised cervical lymph nodes to which they drain play significant roles in the induction of immunological tolerance and of adaptive immunological responses in the CNS. Understanding the afferent and efferent arms of the CNS lymphatic system will be valuable for the development of therapeutic strategies for diseases such as MS.
Meningeal lymphatic vessels (MLVs) contribute to waste product elimination and immune surveillance in brain tissues. MLVs were identified in the dorsal and caudo-basal regions of the dura mater, where they ensure the clearance of cerebrospinal fluid (CSF). Whether MLVs exist in the complex anterior part of the murine and human skull, and how they connect with the glymphatic system and extracranial lymphatic vasculature remained unclear. Here, we generated three-dimensional (3D) maps of MLV drainage by light-sheet fluorescence microscopy (LSFM) imaging of mouse whole-head preparations following fluorescent OVA-A555 tracer injections into the CSF. In humans, we performed real-time magnetic resonance vessel wall imaging (MR-VWI) after systemic gadobutrol injections. We observed a conserved 3D-anatomy of MLVs in mice and humans, and we discovered an extended anterior network around the dural cavernous sinus including multiple capillary beds and exit routes through the foramina of emissa...
Frontiers in Pharmacology, 2023
Background: Fluids, solutes and immune cells have been demonstrated to drain from the brain and surrounding structures to the cervical lymph vessels and nodes in the neck via meningeal lymphatics, nasal lymphatics and/or lymphatic vessels associated with cranial nerves. A method to cannulate the efferent cervical lymph duct for continuous cervical lymph fluid collection in rodents has not been described previously and would assist in evaluating the transport of molecules and immune cells from the head and brain via the lymphatics, as well as changes in lymphatic transport and lymph composition with different physiological challenges or diseases. Aim: To develop a novel method to cannulate and continuously collect lymph fluid from the cervical lymph duct in rats and to analyze the protein, lipid and immune cell composition of the collected cervical lymph fluid. Methods: Male Sprague-Dawley rats were cannulated at the carotid artery with or without cannulation or ligation at the cervical lymph duct. Samples of blood, whole lymph and isolated lipoprotein fractions of lymph were collected and analyzed for lipid and protein composition using commercial kits. Whole lymph samples were centrifuged and isolated pellets were stained and processed for flow cytometry analysis of CD3 + , CD4 + , CD8a + , CD45R + (B220) and viable cell populations. Results: Flow rate, phospholipid, triglyceride, cholesterol ester, free cholesterol and protein concentrations in cervical lymph were 0.094 ± 0.014 mL/h, 0.34 ± 0.10, 0.30 ± 0.04, 0.07 ± 0.02, 0.02 ± 0.01 and 16.78 ± 2.06 mg/mL, respectively. Protein was mostly contained within the non-lipoprotein fraction but all lipoprotein types were also present. Flow cytometry analysis of cervical lymph showed that 67.1 ± 7.4% of cells were CD3 + /CD4 + T lymphocytes, 5.8 ± 1.6% of cells were CD3 + /CD8 + T lymphocytes, and 10.8 ± 4.6% of cells were CD3-/CD45R + B lymphocytes. The remaining 16.3 ± 4.6% cells were CD3-/CD45and identified as non-lymphocytes. Conclusion: Our novel cervical lymph cannulation method enables quantitative analysis of the lymphatic transport of immune cells and molecules in the cervical lymph of rats for the first time. This valuable tool will enable more detailed quantitative analysis of changes to cervical lymph composition and transport in health and disease, and could be a valuable resource for discovery of biomarkers or therapeutic targets in future studies.