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Neuronal Serpina3n is an endogenous protector against blood brain barrier damage following cerebral ischemic stroke

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Li, Fengshi, Zhang, Yueman, Li, Ruqi, Li, Yan, Ding, Shenghao, Zhou, Jianpo, Huang, Tianchen, Chen, Chen, Lu, Bingwei, Yu, Weifeng, Boltze, Johannes, Li, Peiying and Wan, Jieqing (2023) Neuronal Serpina3n is an endogenous protector against blood brain barrier damage following cerebral ischemic stroke. Journal of Cerebral Blood Flow & Metabolism, 43 (2). pp. 241-257. doi:10.1177/0271678X221113897 ISSN 0271-678X.

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Official URL: https://doi.org/10.1177/0271678X221113897

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Abstract

Ischemic stroke results in blood-brain barrier (BBB) disruption, during which the reciprocal interaction between ischemic neurons and components of the BBB appears to play a critical role. However, the underlying mechanisms for BBB protection remain largely unknown. In this study, we found that Serpina3n, a serine protease inhibitor, was significantly upregulated in the ischemic brain, predominantly in ischemic neurons from 6 hours to 3 days after stroke. Using neuron-specific adeno-associated virus (AAV), intranasal delivery of recombinant protein, and immune-deficient Rag1-/- mice, we demonstrated that Serpina3n attenuated BBB disruption and immune cell infiltration following stroke by inhibiting the activity of granzyme B (GZMB) and neutrophil elastase (NE) secreted by T cells and neutrophils. Furthermore, we found that intranasal delivery of rSerpina3n significantly attenuated the neurologic deficits after stroke. In conclusion, Serpina3n is a novel ischemic neuron-derived proteinase inhibitor that counterbalances BBB disruption induced by peripheral T cell and neutrophil infiltration after ischemic stroke. These findings reveal a novel endogenous protective mechanism against BBB damage with Serpina3n being a potential therapeutic target in ischemic stroke.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
R Medicine > RC Internal medicine
Divisions: Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Cerebral ischemia, Cerebral ischemia -- Treatment , Blood-brain barrier, Serine proteinases -- Inhibitors, Leucocyte elastase
Journal or Publication Title: Journal of Cerebral Blood Flow & Metabolism
Publisher: Sage Publications Ltd.
ISSN: 0271-678X
Official Date: February 2023
Dates:
DateEvent
February 2023Published
1 December 2022Available
17 June 2022Accepted
Volume: 43
Number: 2
Page Range: pp. 241-257
DOI: 10.1177/0271678X221113897
Status: Peer Reviewed
Publication Status: Published
Reuse Statement (publisher, data, author rights): Li, Fengshi, Zhang, Yueman, Li, Ruqi, Li, Yan, Ding, Shenghao, Zhou, Jianpo, Huang, Tianchen, Chen, Chen, Lu, Bingwei, Yu, Weifeng, Boltze, Johannes, Li, Peiying and Wan, Jieqing (2023) Neuronal Serpina3n is an endogenous protector against blood brain barrier damage following cerebral ischemic stroke. Journal of Cerebral Blood Flow & Metabolism, 43 (2). pp. 241-257 Copyright © 2023 by International Society for Cerebral Blood Flow and Metabolism. Reprinted by permission of SAGE Publications. https://doi.org/10.1177/0271678X221113897
Access rights to Published version: Restricted or Subscription Access
Date of first compliant deposit: 11 July 2022
Date of first compliant Open Access: 11 July 2022
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
81722017[NSFC] National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
91957111[NSFC] National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
81971096[NSFC] National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
82061130224[NSFC] National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
SHDC12019102Shanghai Shen Kang Hospital Development Centerhttp://dx.doi.org/10.13039/501100010167
20181805Shanghai Municipal Education Commissionhttp://dx.doi.org/10.13039/501100003395
20SG17Shanghai Education Development Foundationhttp://dx.doi.org/10.13039/501100003024
20XD1422400Science and Technology Commission of Shanghai Municipalityhttp://dx.doi.org/10.13039/501100003399
NAF\R11\1010Academy of Medical Scienceshttp://dx.doi.org/10.13039/501100000691
2019-01-07-00-01-E00074 Shanghai Municipal Education Commissionhttp://dx.doi.org/10.13039/501100003395
DLY201821Shanghai Jiao Tong Universityhttp://dx.doi.org/10.13039/501100004921
H2018ZDA07Shanghai Jiao Tong Universityhttp://dx.doi.org/10.13039/501100004921
17411954000Science and Technology Commission of Shanghai Municipalityhttp://dx.doi.org/10.13039/501100003399
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