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Meningeal lymphatic ablation reduces ischemic stroke-induced inflammation via reprograming transcriptome profiling in cervical lymph nodes [scRNA-seq]

ABSTRACT: Meningeal lymphatic system governs immune cell trafficking in the brain via brain-to-cervical lymph node (CLN) pathway. However, the role of meningeal lymphatics in brain–CLN axis after stroke remains unclear. Here, we showed that meningeal lymphatic ablation (MLA) reduced brain infarct and neuronal loss levels and inhibited inflammatory pathways in the hippocampus after MCAO–reperfusion. Single-cell transcriptome analysis demonstrated that MLA reduced monocyte/macrophage and polymorphonuclear cell counts and T and natural killer cell effector function. MLA reprogrammed the transcriptome profile related to chemotaxis and leukocyte migration in CLN LECs and downregulated expression of the CCN1 in floor LECs. Mechanistically, MLA inhibited inflammatory macrophage infiltration by repressing CCN1 and CD147 (thromboinflammatory marker) expression in blood vessels, thus inhibiting detrimental inflammatory responses. Blockade of VEGF-C-mediated signaling in meningeal lymphatic system improved memory function after ischemic stroke. Collectively, MLA reprograms the LEC transcriptome and inhibits CCN1-mediated proinflammatory responses during poststroke brain–CLN signaling.

ORGANISM(S): Mus musculus

PROVIDER: GSE216703 | GEO | 2025/10/24

REPOSITORIES: GEO

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Project description:Aging is a major risk factor for many neurological pathologies, including Alzheimer’s disease (AD). However, the mechanisms underlying brain aging and cognitive decline remain elusive. Body tissues are perfused by interstitial fluid (ISF), which is locally reabsorbed via the lymphatic vascular network. In contrast, the parenchyma of the central nervous system (CNS) is devoid of lymphatic vasculature; in the brain, removal of cellular debris and toxic molecules, such as amyloid beta (A) peptides, is mediated by a combination of transcellular mechanisms of transport across the blood−brain and blood−cerebrospinal fluid (CSF) barriers, phagocytosis and digestion by resident microglia and recruited monocytes/macrophages, and CSF influx and ISF efflux through a paravascular route. The recent characterization of meningeal lymphatic vessels prompted a reassessment of the conventional pathways of CNS waste clearance. The role of this vasculature in brain function, specifically in the context of aging and AD, is still poorly understood. Here we show that meningeal lymphatic vessels play an essential role in maintaining brain homeostasis by draining macromolecules from the CNS (CSF and ISF) into the cervical lymph nodes. Using pharmacological, surgical, and genetic models we show that impairment of meningeal lymphatic function in adult mice slows paravascular influx of CSF macromolecules and efflux of ISF macromolecules, and induces cognitive impairment. Treatment with a lymphangiogenic factor, vascular endothelial growth factor C (VEGF-C), enhances meningeal lymphatic drainage of CSF macromolecules, improving brain perfusion and learning and memory performance in aged mice. Disruption of meningeal lymphatic vessels in transgenic mouse models of AD promotes amyloid deposition in the meninges, which closely correlates with human meningeal pathology, and aggravates overall disease severity. Our findings suggest that meningeal lymphatic dysfunction may be an aggravating factor in AD pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.

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Meningeal lymphatic ablation reduces ischemic stroke-induced inflammation via reprograming transcriptome profiling in cervical lymph nodes [scRNA-seq]

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