Subdural haematomas drain into the extracranial lymphatic system through the meningeal lymphatic vessels.
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ABSTRACT:
SUBMITTER: Liu X
PROVIDER: S-EPMC7023797 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The recent discovery of meningeal lymphatic vessels (LVs) has raised interest in their possible involvement in neuropathological processes, yet little is known about their development or maintenance. We show here that meningeal LVs develop postnatally, appearing first around the foramina in the basal parts of the skull and spinal canal, sprouting along the blood vessels and cranial and spinal nerves to various parts of the meninges surrounding the central nervous system (CNS). VEGF-C, expressed mainly in vascular smooth muscle cells, and VEGFR3 in lymphatic endothelial cells were essential for their development, whereas VEGF-D deletion had no effect. Surprisingly, in adult mice, the LVs showed regression after VEGF-C or VEGFR3 deletion, administration of the tyrosine kinase inhibitor sunitinib, or expression of VEGF-C/D trap, which also compromised the lymphatic drainage function. Conversely, an excess of VEGF-C induced meningeal lymphangiogenesis. The plasticity and regenerative potential of meningeal LVs should allow manipulation of cerebrospinal fluid drainage and neuropathological processes in the CNS.
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Project description:Recent studies have shown that meningeal lymphatic vessels (MLVs), which are located both dorsally and basally beneath the skull, provide a route for draining macromolecules and trafficking immune cells from the central nervous system (CNS) into cervical lymph nodes (CLNs), and thus represent a potential therapeutic target for treating neurodegenerative and neuroinflammatory diseases. However, the roles of MLVs in brain tumor drainage and immunity remain unexplored. Here we show that dorsal MLVs undergo extensive remodeling in mice with intracranial gliomas or metastatic melanomas. RNA-seq analysis of MLV endothelial cells revealed changes in the gene sets involved in lymphatic remodeling, fluid drainage, as well as inflammatory and immunological responses. Disruption of dorsal MLVs alone impaired intratumor fluid drainage and the dissemination of brain tumor cells to deep CLNs (dCLNs). Notably, the dendritic cell (DC) trafficking from intracranial tumor tissues to dCLNs decreased in mice with defective dorsal MLVs, and increased in mice with enhanced dorsal meningeal lymphangiogenesis. Strikingly, disruption of dorsal MLVs alone, without affecting basal MLVs or nasal LVs, significantly reduced the efficacy of combined anti-PD-1/CTLA-4 checkpoint therapy in striatal tumor models. Furthermore, mice bearing tumors overexpressing VEGF-C displayed a better response to anti-PD-1/CTLA-4 combination therapy, and this was abolished by CCL21/CCR7 blockade, suggesting that VEGF-C potentiates checkpoint therapy via the CCL21/CCR7 pathway. Together, the results of our study not only demonstrate the functional aspects of MLVs as classic lymphatic vasculature, but also highlight that they are essential in generating an efficient immune response against brain tumors.
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Project description:Gouty Arthritis (GA) is caused by urate deposition in the joint capsule, cartilage, bone, and surrounding tissues to trigger recurrent attacks of acute joint inflammation. However, the clearance mechanism of urate deposition is still not clear. We aimed to investigate whether lymphatics vessels can drain monosodium and involve in the immune process of GA. Methods: Inguinal lymph nodes (LNs) in 4 normal volunteers and 4 patients with acute flare of GA were examined by ultrasound. Acute and chronic GA flare mouse models were established by intra-footpad administrations of monosodium urate (MSU) for 1 week or 1 month. Mice were treated with VEGFR-3 inhibitor or undergone popliteal lymph node (PLN) excision or PLN macrophage depletion. The severity of foot inflammation, lymphatic draining function, concentration of uric acid (UA), and macrophage population were examined. Macrophages were co-cultured with MSU-treated lymphatic endothelial cells (LECs) and differential gene expression of LECs was assessed by Agilent gene expression microarray. Results: 1) Draining LNs were enlarged in patients with GA flare and GA mouse models. 2) The lymphatic function and structure were abnormal in GA mouse models. 3) Acute GA mice had elevated UA levels in draining LNs, but not in the serum, while chronic GA mice had elevated UA levels in both LNs and serum. 4) Blockade of VEGFR-3 reduced foot inflammation in chronic GA mice. 5) MSU induces pro-inflammatory polarization of macrophages by inducing LEC inflammation. 6) PLN local depletion of macrophages or removal of PLNs alleviated foot inflammation in GA. Conclusions: Lymphatics drain MSU to the draining LNs to clear deposited urate in the distal extremity and induce LECs to stimulate macrophage pro-inflammatory response during GA. We have identified a novel mechanism about MSU clearance and pro-inflammatory macrophage activation, and provided possible therapeutic approach for GA.
2022-04-02 | GSE199950 | GEO
Project description:Recently, the presence of lymphatics has been demonstrated and characterized in the dura mater, which is in contrast to the well-accepted view indicating the lack of a classical lymphatic drainage system of the central nervous system (CNS). Moreover, the role of meningeal lymphatics in the pathogenesis of Alzheimer's disease and multiple sclerosis was suggested. However, the possible regulators of the developmental program and function of meningeal lymphatics remain unclear. Here, we aimed at characterizing the lymph flow dependence of the developmental program and function of the meningeal lymphatics. First, we demonstrated that lymphatics present in the dura mater are involved in the uptake and transport of macromolecules from the CNS. Meningeal lymphatics develop during the postnatal period which process involves the maturation of the vessels. The formation of mature meningeal lymphatics coincides with the increase of the drainage of macromolecules from the CNS to the deep cervical lymph nodes. Importantly, the structural remodeling and maturation of meningeal lymphatics is impaired in Plcγ2 -/- mice with reduced lymph flow. Furthermore, macromolecule uptake and transport by the meningeal lymphatics are also affected in Plcγ2 -/- mice. Collectively, lymph flow-induced mechanical forces are required for the postnatal formation of mature and functional meningeal lymphatic vessels. Defining lymph flow-dependence of the development and function of meningeal lymphatics may lead to better understanding of the pathogenesis of neurological diseases including Alzheimer's disease and multiple sclerosis.
| S-EPMC6970982 | biostudies-literature
Project description:BACKGROUND:Chronic subdural hematoma (cSDH) is one of the most frequent neurosurgical conditions affecting elderly people and is associated with substantial morbidity and mortality. The use of a subdural drain (SDD) after burr-hole trepanation for cSDH was proven to reduce recurrence and mortality at 6 months. To date in neurosurgery practice, evidence-based guidelines on whether an SDD or subperiosteal drain (SPD) should be used do not exist. Currently both methods are being practiced depending on the institute and/or the practicing neurosurgeon. OBJECTIVE:The aim of this study is to compare the reoperation rates after burr-hole trepanation and insertion of an SPD or SDD in patients with cSDH. METHODS:This is a prospective, noninferiority, multicenter, randomized controlled trial designed to include 220 patients over the age of 18 years presenting with a symptomatic cSDH verified on cranial computed tomography or magnetic resonance imaging who are to undergo surgical evacuation with burr-hole trepanation. After informed consent is obtained, patients are randomly allocated to an SPD or SDD group. The primary endpoint is recurrence indicating a reoperation within 12 months. RESULTS:This research is investigator-initiated and has received ethics approval. Patient recruitment started in April 2013, and we expect all study-related activities to be completed by the end of 2016 or beginning of 2017. CONCLUSIONS:To date, evidence-based recommendations concerning the operative treatment of cSDH are sparse. Results of this research are expected to have applications in evidence-based practice for the increasing number of patients suffering from cSDH and possibly lead to more efficient treatment of this disease with fewer postoperative complications. TRIAL REGISTRATION:ClinicalTrials.gov NCT01869855; https://clinicaltrials.gov/ct2/show/NCT01869855 (Archived by WebCite at http://www.webcitation.org/6fNK4Jlxk).
| S-EPMC4841895 | biostudies-literature
Project description:One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
| S-EPMC4506234 | biostudies-literature
Project description: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 lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.
| S-EPMC6214619 | biostudies-literature
Project description:BACKGROUND:Previously, we showed that lymphatic vessels (LVs) formed detours after lymphatic obstruction, contributing to preventing lymphedema. In this study, we developed detours using lymphatic ligation in mice and we identified the detours histologically. METHODS AND RESULTS:Under anesthesia, both hindlimbs in mice were subcutaneously injected with Evans blue dye to detect LVs. We tied the right collecting LV on the abdomen that passes through the inguinal lymph node (LN) at two points. The right and left sides comprised the operation and sham operation sides, respectively. Lymphography was performed to investigate the lymph flow after lymphatic ligation until day 30, using a near-infrared fluorescence imaging system. Anti-podoplanin antibody and 5-ethynyl-2'-deoxyuridine (EdU) were used to detect LVs and lymphangiogenesis. Within 30 days, detours had developed in 62.5% of the mice. Detours observed between two ligation sites were enlarged and irregular in shape. Podoplanin+ LVs, which were located in the subcutaneous tissue of the upper panniculus carnosus muscle, connected to collecting LVs at the upper portion from the cranial ligation site and at the lower portion from the caudal ligation site. EdU+ cells were not observed in these detours. The sham operation side showed normal lymph flow and did not show enlarged pre-collecting LVs until day 30. CONCLUSIONS:Detours after lymphatic ligation were formed not by lymphangiogenesis but through an enlargement of pre-collecting LVs that functioned as collecting LVs after lymphatic ligation. Further studies are required to explore the developmental mechanism of the lymphatic detour for treatment and effective care of lymphedema in humans.
| S-EPMC6961945 | biostudies-literature
Project description:Human vascular malformations cause disease as a result of changes in blood flow and vascular hemodynamic forces. Although the genetic mutations that underlie the formation of many human vascular malformations are known, the extent to which abnormal blood flow can subsequently influence the vascular genetic program and natural history is not. Loss of the SH2 domain-containing leukocyte protein of 76 kDa (SLP76) resulted in a vascular malformation that directed blood flow through mesenteric lymphatic vessels after birth in mice. Mesenteric vessels in the position of the congenital lymphatic in mature Slp76-null mice lacked lymphatic identity and expressed a marker of blood vessel identity. Genetic lineage tracing demonstrated that this change in vessel identity was the result of lymphatic endothelial cell reprogramming rather than replacement by blood endothelial cells. Exposure of lymphatic vessels to blood in the absence of significant flow did not alter vessel identity in vivo, but lymphatic endothelial cells exposed to similar levels of shear stress ex vivo rapidly lost expression of PROX1, a lymphatic fate-specifying transcription factor. These findings reveal that blood flow can convert lymphatic vessels to blood vessels, demonstrating that hemodynamic forces may reprogram endothelial and vessel identity in cardiovascular diseases associated with abnormal flow.
| S-EPMC3366395 | biostudies-literature
Project description:The pathways of circulation and clearance of cerebrospinal fluid (CSF) in the spine have yet to be elucidated. We have recently shown with dynamic in vivo imaging that routes of outflow of CSF in mice occur along cranial nerves to extracranial lymphatic vessels. Here, we use near-infrared and magnetic resonance imaging to demonstrate the flow of CSF tracers within the spinal column and reveal the major spinal pathways for outflow to lymphatic vessels in mice. We found that after intraventricular injection, a spread of CSF tracers occurs within both the central canal and the spinal subarachnoid space toward the caudal end of the spine. Outflow of CSF tracers from the spinal subarachnoid space occurred predominantly from intravertebral regions of the sacral spine to lymphatic vessels, leading to sacral and iliac LNs. Clearance of CSF from the spine to lymphatic vessels may have significance for many conditions, including multiple sclerosis and spinal cord injury.
| S-EPMC6829589 | biostudies-literature