Astrocyte glutathione maintains endothelial barrier stability
dc.contributor.author
Huang, Sheng-Fu
dc.contributor.author
Othman, Alaa
dc.contributor.author
Koshkin, Alexey
dc.contributor.author
Fischer, Sabrina
dc.contributor.author
Fischer, David
dc.contributor.author
Zamboni, Nicola
dc.contributor.author
Ono,
Katsuhiko
dc.contributor.author
Sawa, Tomohiro
dc.contributor.author
Ogunshola, Omolara O.
dc.date.accessioned
2022-01-18T08:39:20Z
dc.date.available
2022-01-18T08:39:20Z
dc.date.issued
2020-07
dc.identifier.issn
2213-2317
dc.identifier.other
10.1016/j.redox.2020.101576
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/526432
dc.identifier.doi
10.3929/ethz-b-000418746
dc.description.abstract
Blood-brain barrier (BBB) impairment clearly accelerates brain disease progression. As ways to prevent injury-induced barrier dysfunction remain elusive, better understanding of how BBB cells interact and modulate barrier integrity is needed. Our metabolomic profiling study showed that cell-specific adaptation to injury correlates well with metabolic reprogramming at the BBB. In particular we noted that primary astrocytes (AC) contain comparatively high levels of glutathione (GSH)-related metabolites compared to primary endothelial cells (EC). Injury significantly disturbed redox balance in EC but not AC motivating us to assess 1) whether an AC-EC GSH shuttle supports barrier stability and 2) the impact of GSH on EC function. Using an isotopic labeling/tracking approach combined with Time-of-Flight Mass Spectrometry (TOF-MS) we prove that AC constantly shuttle GSH to EC even under resting conditions - a flux accelerated by injury conditions in vitro. In correlation, co-culture studies revealed that blocking AC GSH generation and secretion via siRNA-mediated γ-glutamyl cysteine ligase (GCL) knockdown significantly compromises EC barrier integrity. Using different GSH donors, we further show that exogenous GSH supplementation improves barrier function by maintaining organization of tight junction proteins and preventing injury-induced tight junction phosphorylation. Thus the AC GSH shuttle is key for maintaining EC redox homeostasis and BBB stability suggesting GSH supplementation could improve recovery after brain injury.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Elsevier
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.subject
Neurovascular unit
en_US
dc.subject
Metabolic communication
en_US
dc.subject
Barrier stability
en_US
dc.subject
Tight junction
en_US
dc.subject
Blood-brain barrier
en_US
dc.subject
Redox balance
en_US
dc.title
Astrocyte glutathione maintains endothelial barrier stability
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
dc.date.published
2020-05-19
ethz.journal.title
Redox Biology
ethz.journal.volume
34
en_US
ethz.pages.start
101576
en_US
ethz.size
11 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Amsterdam
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02538 - Institut für Molekulare Systembiologie / Institute for Molecular Systems Biology::08839 - Zamboni, Nicola (Tit.-Prof.)
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02538 - Institut für Molekulare Systembiologie / Institute for Molecular Systems Biology::08839 - Zamboni, Nicola (Tit.-Prof.)
ethz.date.deposited
2020-06-08T02:39:56Z
ethz.source
BATCH
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2022-01-18T08:39:29Z
ethz.rosetta.lastUpdated
2023-02-06T23:50:49Z
ethz.rosetta.versionExported
true
dc.identifier.olduri
http://hdl.handle.net/20.500.11850/525515
dc.identifier.olduri
http://hdl.handle.net/20.500.11850/418746
ethz.COinS
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