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Enhanced meningeal lymphangiogenesis and glymphatic drainage ameliorates neuroinflammation and white matter demyelination

ABSTRACT: White matter hyperintensity (WMH) is a pressing global medical issue linked to cognitive decline and stroke risk. Despite its significance, the underlying mechanisms remain unclear. Here, we directly demonstrated in humans that high WMH burden correlated with delayed glymphatic pathway drainage. Additionally, a longitudinal cohort study revealed that glymphatic dysfunction predicted WMH progression. Next, in a rat model of WMH, we confirmed the presence of impaired lymphangiogenesis and glymphatic drainage, followed by elevated microglial activation and white matter demyelination. Notably, enhancing meningeal lymphangiogenesis and glymphatic drainage through adenoviral delivery of Vascular Endothelial Growth Factor-C (VEGF-C) mitigated microglial gliosis and white matter demyelination. Conversely, blocking the growth of meningeal lymphatics with a VEGF-C trap strategy exacerbated these changes. Our findings highlight the role of meningeal lymphatics and glymphatic pathway dysfunction in aggravating brain white matter injury and advancing WMH, providing a potential novel strategy for WMH prevention and treatment.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE240229 | GEO | 2024/07/17

REPOSITORIES: GEO

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Enhanced meningeal lymphatic drainage ameliorates lipopolysaccharide-induced brain injury in aged mice

Project description:Sepsis-associated encephalopathy (SAE) is an acute cerebral dysfunction caused by sepsis. Neuroinflammation induced by sepsis is considered a potential mechanism of SAE; however, very little is known about the role of the meningeal lymphatic system in SAE. The aged mice with SAE showed a significant decrease in the drainage of OVA-647 into the dCLNs and the coverage of the Lyve-1 in the meningeal lymphatic, indicating that sepsis impaired meningeal lymphatic drainage and morphology. The meningeal lymphatic function of aged mice was more vulnerable to sepsis in comparison to young mice. Sepsis also decreased the protein levels of caspase-3 and PSD95, which was accompanied by reductions in the activity of hippocampal neurons. Microglia were significantly activated in the hippocampus of SAE mice, which was accompanied by an increase in neuroinflammation, as indicated by increases in interleukin-1 beta, interleukin-6 and Iba1 expression. Cognitive function was impaired in aged mice with SAE. However, the injection of AAV1-VEGF-C significantly increased coverage in the lymphatic system and tracer dye uptake in dCLNs, suggesting that AAV1-VEGF-C promotes meningeal lymphangiogenesis and drainage. Furthermore, AAV1-VEGF-C reduced microglial activation and neuroinflammation and improved cognitive dysfunction. Improvement of meningeal lymphatics also reduced sepsis-induced expression of disease-associated genes in aged mice. Pre-existing lymphatic dysfunction by ligating bilateral dCLNs aggravated sepsis-induced neuroinflammation and cognitive impairment.

2023-11-30 | GSE247222 | GEO

RNA-seq analysis of brain tissue treated by VEGFC in BDL-induced cirrhotic rat with hepatic encephalopathy

Project description:Aims: Hepatic encephalopathy (HE) is a serious neurological complication in patients with liver cirrhosis. Nothing is known about the role of the meningeal lymphatic system in HE. We tested our hypothesis that enhancement of meningeal lymphatic drainage could decrease neuroinflammation and ameliorate HE. Methods: A 4-week bile duct ligation (BDL) model was used to develop cirrhosis with HE in rats. Brain inflammation in patients with HE was evaluated using archived GSE41919. Motor function of rats was assessed by the rotarod test. AAV8-VEGF-C was injected into the cisterna magna of BDL rats one day after surgery to induce meningeal lymphangiogenesis. Results: Cirrhotic rats with HE showed significantly increased microglia activation in the middle region of the cortex (p<0.001) as well as increased neuroinflammation as indicated by significant increases in IL-1, INF, TNF and Iba1 expression in at least one of the three regions of the cortex. Motor function was also impaired in rats with HE (p<0.05). Human brains of cirrhotic patients with HE also exhibited upregulation of pro-inflammatory genes (NF-κβ, Iba1, TNFα and IL-1β) (n=6). AAV8-VEGF-C injection significantly increased meningeal lymphangiogenesis (p=0.035) and tracer dye uptake in the anterior and middle regions of the cortex (p=0.006 & 0.003, respectively), their corresponding meninges (p=0.086 & 0.006, respectively) and the draining lymph nodes (p=0.02). Further, AAV8-VEGF-C decreased microglia activation (p<0.001) and neuroinflammation, and ameliorated motor dysfunction (p=0.024). Conclusion: Promoting meningeal lymphatic drainage and enhancing waste clearance improves HE. Manipulation of meningeal lymphangiogenesis could be a new therapeutic strategy for the treatment of HE.

2023-04-23 | GSE149227 | GEO

Meningeal lymphatic vasculature mediates cervical lymph node metastasis of brain tumors through VEGF-C/VEGFR3/eNOS signaling pathway

Project description:Purpose: The rediscovery of meningeal lymphatic vessels (MLVs) suggests a potential linkage between brain tumors and cervical lymph nodes (LNs). In this study, we investigated whether and how meningeal lymphatics regulate the metastasis of brain tumor cells. Experimental Design: We first examined the pattern of MLVs and LNs after tumor cells were injected into the cisterna magna (i.c.m.) or subdural space of mice. The meninges were isolated and analyzed by whole-mount immunofluorescence staining. LN metastasis was analyzed by detecting GFP+ tumor cells. Then we used inducible knock-out mice and AAV-VEGF-C delivery system to study the function of MLVs in mediating the metastasis of brain tumor cells. Finally, RNA-seq was used to determine the expression profiles of meningeal lymphatic endothelial cells (mLECs) in mice with or without tumors. The roles of the endothelial nitric oxide synthetase (eNOS) were evaluated both genetically and pharmacologically in vivo. Results: Meningeal lymphangiogenesis induced by GL261 and B16 tumors was correlated with dCLN swelling and metastasis. dCLN metastasis was suppressed in MLV-defective mice, while promoted in AAV-VEGF-C-treated mice. In addition, we found that VEGF-C/VEGFR3 signaling regulated both meningeal and tumor lymphangiogenesis. Tumor-associated mLECs have a distinct transcriptomic signature, which highly express eNOS. Furthermore, genetic or pharmacological inhibition of eNOS significantly suppressed meningeal lymphangiogenesis and dCLN metastasis. Conclusions: The meningeal lymphatic vasculature mediates the metastasis of brain tumors to cervical LNs, mainly through a VEGF-C/VEGFR3-eNOS signaling pathway, suggesting that MLV may be a potential therapeutic target for the extracranial metastasis of brain tumors.

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A functional role of meningeal lymphatics in sex difference of stress susceptibility in mice

Project description:Major depressive disorder is one of the most common mental health conditions. Meningeal lymphatics are essential for drainage of molecules in the cerebrospinal fluid to the peripheral immune system. Their potential role in depression-like behaviour has not been investigated. Here, we show in mice, sub-chronic variable stress as a model of depression-like behaviour impairs meningeal lymphatics in females but not in males. Manipulations of meningeal lymphatics regulate the sex difference in the susceptibility to stress-induced depression- and anxiety-like behaviors in mice, as well as alterations of the medial prefrontal cortex and the ventral tegmental area, brain regions critical for emotional regulation. Together, our findings suggest meningeal lymphatic impairment contributes to susceptibility to stress in mice, and that restoration of the meningeal lymphatics might have potential for modulation of depression-like behaviour.

2022-07-05 | GSE201368 | GEO

Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis

Project description:The goal of this study is to use bulk RNA-sequencing of the right brain hemisphere to observe the effects of TBI in the context of pre-existing meningeal lymphatic dysfunction in mice. We find that pre-existing meningeal lymphatic dysfunction potentiates the inflammatory response to TBI, suggesting an important role for the meningeal lymphatics in injury site drainage and proper recovery.

2020-07-25 | GSE155063 | GEO

Project description:The meningeal lymphatic network—housed within the dural meninges surrounding the brain— is critical for cerebrospinal fluid (CSF) drainage. Through continuous brain interstitial fluid (ISF) mixing with CSF via the glymphatic system, this lymphatic network facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer’s disease (AD), attenuated meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins—including amyloid beta—in the CNS. Alleviating this age-related meningeal lymphatic dysfunction represents a promising therapeutic strategy to alleviate AD pathology. However, the mechanisms underlying this lymphatic decline remain elusive. Here we demonstrate that age-related alterations in meningeal immunity contribute to meningeal lymphatic impairment. Single-cell RNA-sequencing of dural lymphatic endothelial cells in aged mice demonstrated a response signature to the cytokine IFNγ, which was elevated in the aged dura due to meningeal T cell accumulation. Chronic elevation of IFNγ in the meninges of young mice via AAV-mediated overexpression altered lymphatic adherans junctions and impaired CSF drainage to deep cervical lymph nodes—comparable to the deficits observed in aged mice. Direct disruption of lymphatic junctions via CSF-delivered VE-Cadherin disrupting antibodies was sufficient to phenocopy impairments in CSF drainage. Therapeutically, IFNγ neutralization in aged mice alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable therapeutic target to normalize CSF drainage in aged mice and alleviate the pathology in AD mice associated with impaired waste removal.

2023-03-10 | GSE217312 | GEO

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VEGF-C prophylaxis promotes lymphatic drainage, microglia modulation, and neuroprotection in response to stroke injury

Project description:Meningeal lymphatic vessels (MLVs) promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelial growth factor-C (VEGF-C) regulates MLV development and maintenance and has therapeutic potential for treating neurological disorders. Herein, we investigated the effects of VEGF-C overexpression on brain fluid drainage and ischemic stroke outcomes in mice. Intra-cerebrospinal administration of an adeno-associated virus expressing mouse full-length VEGF-C (AAV-mVEGF-C) increased CSF drainage to the deep cervical lymph nodes (dCLNs) by enhancing lymphatic growth, and upregulated neuroprotective signaling pathways identified by single nuclei RNA sequencing of brain cells. In a mouse model of ischemic stroke, AAV-mVEGF-C pretreatment reduced stroke injury and ameliorated motor performances in the subacute stage, associated with mitigated microglia-mediated inflammation and increased BDNF signaling in brain cells. Neuroprotective effects of VEGF-C were lost upon ligation of the dCLN afferent lymphatics, and not mimicked by acute post-stroke VEGF-C injection. We conclude that VEGF-C prophylaxis promotes multiple vascular, immune, and neural responses that culminate in a protection against neurological damage in acute ischemic stroke.

2024-01-18 | GSE253051 | GEO

Effect of VEGF-C treatment on sorted brain microglia/macrophages

2024-02-27 | GSE252622 | GEO

CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature [2D2 T cells]

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.

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