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Cited by 52Barrier Structure and Function StudiesRedox biology and oxidative stressSulfur Compounds in Biology

Astrocyte glutathione maintains endothelial barrier stability

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Huang, Sheng-Fu, Othman, Alaa, Koshkin, Alexey, Fischer, Sabrina, Fischer, David, Zamboni, Nicola, Ono, Katsuhiko, Sawa, Tomohiro +1 more·2020·Redox Biology
DOI 10.1016/j.redox.2020.101576PMC PMC7267730
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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.

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  • The supply of GSH precursors from astrocytes appears not to be exclusive for neurons as receiving cell type; a similar interaction in GSH metabolism by cysteine supply via GSH export appears to take place between astrocytes and endothelial cells.

    “The supply of GSH precursors from astrocyte appears not to be exclusive for neurons as receiving cell type. A similar interaction in GSH metabolism by cysteine supply via GSH export appears to take place between astrocytes and endothelial cells, and this cysteine shuttle has been reported to help to maintain endothelial barrier stability and integrity (Huang et al. 2020).”

    From Glutathione Metabolism of the Brain—The Role of Astrocytes (2025) · cites this paper as Huang et al. 2020

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  • The cysteine shuttle between astrocytes and endothelial cells helps to maintain endothelial barrier stability and integrity.

    “A similar interaction in GSH metabolism by cysteine supply via GSH export appears to take place between astrocytes and endothelial cells, and this cysteine shuttle has been reported to help to maintain endothelial barrier stability and integrity (Huang et al. 2020).”

    From Glutathione Metabolism of the Brain—The Role of Astrocytes (2025) · cites this paper as Huang et al. 2020

    The Significance section reports that astrocyte-derived glutathione supports endothelial barrier stability and that blocking its transfer increases permeability. The Discussion says the proposed cysteine-supply mechanism—glutathione breakdown followed by cysteine uptake—was not investigated in detail and remains speculative, so the paper does not establish a cysteine shuttle specifically. (LLM, conf=0.88)

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Authors
Huang, S.-F., Othman, A., Koshkin, A., Fischer, S., Fischer, D., Zamboni, N., Ono, K., Sawa, T., & Ogunshola, O. O.
Affiliations
  • University of Zurich (CH)
  • ETH Zurich (CH)
  • University of Basel (CH)
  • Kumamoto University (JP)
Corresponding author
Ogunshola, Omolara O.
ORCID
Venue
Redox Biology
Publisher
Elsevier BV
Published
2020-07
Volume
34
Pages
101576
ISSN
2213-2317 (ISSN-L)
DOI
10.1016/j.redox.2020.101576
PMC
PMC7267730
OpenAlex
W3028149388
Cited by
52
References
3
Citations by year
2026: 4 · 2025: 11 · 2024: 5 · 2023: 12 · 2022: 12 · 2021: 6 · 2020: 2
FWCI
3.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Redox Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • ETH Zürich Research Collection (cc-by)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • EC
  • AC
  • NAC
  • Swiss National Science Foundation (31003A_170129)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
Keywords
glutathione, astrocytes, endothelial cells, blood-brain barrier, barrier integrity, redox homeostasis, tight junctions, brain injury, astrocyte-endothelial interactions, metabolic reprogramming
MeSH terms
Astrocytes, Blood-Brain Barrier, Glutathione, Tight Junctions, Endothelial Cells

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