CCN1 Is a Therapeutic Target for Reperfused Ischemic Brain Injury
Gilbert Aaron Lee1,2,3,4, Yu-Wei Chang1, Jing-Huei Lai5,6
1Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan.
Insights
Disrupting meningeal lymphatics after ischemic stroke reduced brain injury and improved memory by decreasing harmful inflammation. This highlights CCN1 as a potential therapeutic target for stroke recovery.
Area of Science:
- Neuroscience
- Immunology
- Vascular Biology
Background:
- Ischemic stroke triggers systemic inflammation, leading to neuroinflammation and brain damage.
- Meningeal lymphatics clear waste and immune cells from the brain to cervical lymph nodes (CLNs).
- The function of meningeal lymphatics in regulating systemic inflammation post-ischemia is unclear.
Purpose of the Study:
- To investigate the role of meningeal lymphatics in systemic inflammation after cerebral ischemia-reperfusion.
- To explore the impact of meningeal lymphatic disruption on brain injury and immune cell infiltration.
- To identify molecular mechanisms, including CCN1, involved in this process.
Main Methods:
- Cerebral ischemia-reperfusion model in mice with disrupted meningeal lymphatics.
- Assessment of brain infarct size, neuronal loss, and spatial memory.
- Analysis of immune cell infiltration using flow cytometry and single-cell RNA sequencing.
- Manipulation of CCN1 levels via intraventricular injection and cerebrospinal fluid blocking.
Main Results:
- Disruption of meningeal lymphatics reduced infarct size, neuronal loss, and inflammatory macrophage activity.
- Spatial memory function improved in mice with disrupted meningeal lymphatics.
- Reduced infiltration of neutrophils, monocytes, T cells, and NK cells was observed.
- Meningeal lymphatic disruption altered CLN lymphatic endothelial cell transcriptomes and decreased CCN1 expression.
- CCN1 replenishment exacerbated injury, while CCN1 blockade improved outcomes.
Conclusions:
- Meningeal lymphatics contribute to detrimental inflammation after ischemic stroke.
- CCN1 plays a key role in mediating this inflammation via the brain-CLN axis.
- Targeting CCN1 offers a potential therapeutic strategy for mitigating brain injury and inflammation post-stroke.
Abstract:
Ischemic stroke can lead to systemic inflammation, which can activate peripheral immune cells, causing neuroinflammation and brain injury. Meningeal lymphatics play a crucial role in transporting solutes and immune cells out of the brain and draining them into cervical lymph nodes (CLNs). However, the role of meningeal lymphatics in regulating systemic inflammation during the reperfusion stage after ischemia is not well understood. In this study, we demonstrated that brain infarct size, neuronal loss, and the effector function of inflammatory macrophage subsets were reduced after ischemia-reperfusion and disruption of meningeal lymphatics. Spatial memory function was improved in the late stage of ischemic stroke following meningeal lymphatic disruption. Brain-infiltrating immune cells, including neutrophils, monocytes, and T and natural killer cells, were reduced after cerebral ischemia-reperfusion and meningeal lymphatic disruption. Single-cell RNA sequencing analysis revealed that meningeal lymphatic disruption reprogrammed the transcriptome profile related to chemotaxis and leukocyte migration in CLN lymphatic endothelial cells (LECs), and it also decreased chemotactic CCN1 expression in floor LECs. Replenishment of CCN1 through intraventricular injection increased brain infarct size and neuronal loss, while restoring numbers of macrophages/microglia in the brains of meningeal lymphatic-disrupted mice after ischemic stroke. Blocking CCN1 in cerebrospinal fluid reduced brain infarcts and improves spatial memory function after ischemia-reperfusion injury. In summary, this study indicates that CCN1-mediated detrimental inflammation was alleviated after cerebral ischemia-reperfusion injury and meningeal lymphatic disruption. CCN1 represents a novel therapeutic target for inhibiting systemic inflammation in the brain-CLN axis after ischemia-reperfusion injury.
Related Concept Videos
01:15Ischemic Stroke l: Introduction
01:15Ischemic Stroke ll: Pathophysiology