CCN1 Is a Therapeutic Target for Reperfused Ischemic Brain Injury

Gilbert Aaron Lee^{1

2

3

4}, Yu-Wei Chang¹, Jing-Huei Lai^{5

6}, Tzu-Hao Chang⁷, Shiu-Wen Huang^{1

8

9}, Chih-Hao Yang⁹, Ting-An Shen¹⁰, Wan-Li Lin¹, Ying-Chieh Wu¹, Li-Wen Tseng¹, Sung-Hui Tseng^{11

12}, Yung-Chieh Chen¹³, Yung-Hsiao Chiang^{5

6

14

15}, Cheng-Yu Chen^{16

17

18}

Affiliations

¹ Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan.
² Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
³ Child Development Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
⁴ TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei, Taiwan.
⁵ Core Laboratory of Neuroscience, Office of R&D, Taipei Medical University, Taipei, Taiwan.
⁶ Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan.
⁷ Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei, Taiwan.
⁸ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁹ Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
¹⁰ Bioinformatics Center, Office of Data Science, Taipei Medical University, Taipei, Taiwan.
¹¹ Department of Physical Medicine and Rehabilitation, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
¹² Department of Physical Medicine and Rehabilitation, Taipei Medical University Hospital, Taipei, Taiwan.
¹³ Department of Medical Imaging, Taipei Medical University Hospital, Taipei, Taiwan.
¹⁴ Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan.
¹⁵ Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
¹⁶ Department of Medical Imaging, Taipei Medical University Hospital, Taipei, Taiwan. sandy0932@gmail.com.
¹⁷ Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing Street, Taipei, 110, Taiwan. sandy0932@gmail.com.
¹⁸ Translational Imaging Research Center, College of Medicine, Taipei Medical University, Taipei, Taiwan. sandy0932@gmail.com.

PMID: 39028413
DOI: 10.1007/s12975-024-01279-0

CCN1 Is a Therapeutic Target for Reperfused Ischemic Brain Injury

Gilbert Aaron Lee et al. Transl Stroke Res. 2025 Aug.

. 2025 Aug;16(4):1044-1061.

doi: 10.1007/s12975-024-01279-0. Epub 2024 Jul 19.

Authors

Affiliations

¹ Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan.
² Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
³ Child Development Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
⁴ TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei, Taiwan.
⁵ Core Laboratory of Neuroscience, Office of R&D, Taipei Medical University, Taipei, Taiwan.
⁶ Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan.
⁷ Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei, Taiwan.
⁸ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁹ Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
¹⁰ Bioinformatics Center, Office of Data Science, Taipei Medical University, Taipei, Taiwan.
¹¹ Department of Physical Medicine and Rehabilitation, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
¹² Department of Physical Medicine and Rehabilitation, Taipei Medical University Hospital, Taipei, Taiwan.
¹³ Department of Medical Imaging, Taipei Medical University Hospital, Taipei, Taiwan.
¹⁴ Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan.
¹⁵ Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
¹⁶ Department of Medical Imaging, Taipei Medical University Hospital, Taipei, Taiwan. sandy0932@gmail.com.
¹⁷ Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing Street, Taipei, 110, Taiwan. sandy0932@gmail.com.
¹⁸ Translational Imaging Research Center, College of Medicine, Taipei Medical University, Taipei, Taiwan. sandy0932@gmail.com.

PMID: 39028413
DOI: 10.1007/s12975-024-01279-0

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.

Keywords: CCN1; Ischemic stroke; Lymphatic endothelial cell; Macrophage; Meningeal lymphatics.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics Approval and Consent to Participate: All animal studies were approved by the Institutional Animal Care and Use Committee of Taipei Medical University (IACUC number: LAC-2020–0567). Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests.

References

1. Nour M, Scalzo F, Liebeskind DS. Ischemia-reperfusion injury in stroke. Interv Neurol. 2013;1(3–4):185–99. - PubMed - PMC
1. Stoll G, Nieswandt B. Thrombo-inflammation in acute ischaemic stroke – implications for treatment. Nat Rev Neurol. 2019;15(8):473–81. - PubMed - DOI
1. Rayasam A, et al. Immune responses in stroke: how the immune system contributes to damage and healing after stroke and how this knowledge could be translated to better cures? Immunology. 2018;154(3):363–76. - PubMed - PMC - DOI
1. Louveau A, Da Mesquita S, Kipnis J. Lymphatics in neurological disorders: a neuro-lympho-vascular component of multiple sclerosis and Alzheimer’s disease? Neuron. 2016;91(5):957–73. - PubMed - PMC - DOI
1. Louveau A, et al. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat Neurosci. 2018;21(10):1380–91. - PubMed - PMC - DOI

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

CCN1 Is a Therapeutic Target for Reperfused Ischemic Brain Injury

Affiliations

CCN1 Is a Therapeutic Target for Reperfused Ischemic Brain Injury

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Medical