Astrocyte glutathione maintains endothelial barrier stability.
Barrier stability
Blood-brain barrier
Metabolic communication
Neurovascular unit
Redox balance
Tight junction
Journal
Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
01
03
2020
revised:
28
04
2020
accepted:
10
05
2020
pubmed:
6
6
2020
medline:
22
6
2021
entrez:
6
6
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32502899
pii: S2213-2317(20)30361-X
doi: 10.1016/j.redox.2020.101576
pmc: PMC7267730
pii:
doi:
Substances chimiques
Glutathione
GAN16C9B8O
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101576Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare no competing interests.
Références
J Neurol Neurosurg Psychiatry. 2008 Jul;79(7):774-7
pubmed: 17991703
Biol Chem. 2009 Mar;390(3):191-214
pubmed: 19166318
Biochem Biophys Res Commun. 2003 Mar 7;302(2):324-9
pubmed: 12604349
Transplant Proc. 2014 May;46(4):1180-5
pubmed: 24815155
Brain Res Dev Brain Res. 2001 Sep 23;130(1):123-32
pubmed: 11557101
Eur J Biochem. 1991 Dec 5;202(2):421-9
pubmed: 1684747
Int J Cell Biol. 2012;2012:434971
pubmed: 22745639
J Cereb Blood Flow Metab. 2009 Jun;29(6):1099-108
pubmed: 19319148
Clin Toxicol (Phila). 2011 Oct;49(8):720-8
pubmed: 21970770
J Cell Physiol. 2014 Aug;229(8):1096-105
pubmed: 24375098
J Anat. 2002 Jun;200(6):629-38
pubmed: 12162730
Arch Physiol Biochem. 2007 Oct-Dec;113(4-5):234-58
pubmed: 18158646
Exp Lung Res. 2010 Feb;36(1):45-56
pubmed: 20128681
Biochem Pharmacol. 2002 Sep;64(5-6):1057-64
pubmed: 12213605
J Biol Chem. 2015 Apr 3;290(14):8778-88
pubmed: 25713140
Am J Physiol Cell Physiol. 2000 Jul;279(1):C21-30
pubmed: 10898713
PLoS One. 2014 Jan 08;9(1):e82331
pubmed: 24416140
Neurochem Res. 1999 Dec;24(12):1507-14
pubmed: 10591399
Prog Neurobiol. 2000 Dec;62(6):649-71
pubmed: 10880854
Antioxidants (Basel). 2017 Aug 03;6(3):
pubmed: 28771170
Neurology. 2001 Oct 23;57(8):1515-7
pubmed: 11673605
J Cereb Blood Flow Metab. 2007 Nov;27(11):1766-91
pubmed: 17579656
Antioxid Redox Signal. 2011 Sep 1;15(5):1305-23
pubmed: 21294658
J Appl Physiol (1985). 2004 Oct;97(4):1358-66
pubmed: 15180977
Nat Rev Neurol. 2018 Mar;14(3):133-150
pubmed: 29377008
Br J Pharmacol. 2014 Mar;171(5):1210-30
pubmed: 24641185
Front Biosci. 2008 May 01;13:7210-26
pubmed: 18508729
Sci Rep. 2020 May 8;10(1):7760
pubmed: 32385409
J Cell Physiol. 1994 Apr;159(1):101-13
pubmed: 7908023
Free Radic Biol Med. 2017 May;106:69-79
pubmed: 28189853
Nat Commun. 2012 Mar 06;3:718
pubmed: 22395609
Brain Res. 2000 Jan 3;852(1):191-7
pubmed: 10661512
Cell Calcium. 2004 Sep-Oct;36(3-4):295-302
pubmed: 15261485
J Neurochem. 2011 Apr;117(2):333-45
pubmed: 21291474
J Neurosci. 2006 Oct 11;26(41):10514-23
pubmed: 17035536
J Cell Physiol. 2009 Mar;218(3):612-22
pubmed: 19016245
J Alzheimers Dis. 2015;45(2):395-405
pubmed: 25589719
Exp Neurobiol. 2014 Mar;23(1):93-103
pubmed: 24737944
Fluids Barriers CNS. 2015 Feb 17;12:4
pubmed: 25879623
Brain Res. 1992 Jan 13;569(2):275-80
pubmed: 1347243
Anal Chem. 2011 Sep 15;83(18):7074-80
pubmed: 21830798
J Cereb Blood Flow Metab. 2011 Feb;31(2):693-705
pubmed: 20827262
Am J Physiol. 1997 Dec;273(6):C1859-67
pubmed: 9435490
Eur J Cell Biol. 2011 Apr;90(4):323-32
pubmed: 21168935
Neurology. 1998 Dec;51(6):1562-6
pubmed: 9855502
IUBMB Life. 2018 Jul;70(7):585-592
pubmed: 29667297
ACS Appl Mater Interfaces. 2012 Jun 27;4(6):3177-83
pubmed: 22646097
Chem Commun (Camb). 2008 Dec 28;(48):6570-2
pubmed: 19057782
Glia. 2005 Jun;50(4):362-88
pubmed: 15846808
Circ Res. 2015 Mar 27;116(7):1231-44
pubmed: 25814684
J Neurochem. 2000 Apr;74(4):1434-42
pubmed: 10737599
J Cereb Blood Flow Metab. 2009 Dec;29(12):1933-45
pubmed: 19654589
Stroke. 2018 May;49(5):1223-1231
pubmed: 29643256
PLoS One. 2016 Jun 16;11(6):e0157602
pubmed: 27309537
Biochemistry. 1999 Jun 8;38(23):7421-30
pubmed: 10360939
Biochim Biophys Acta. 2012 May;1822(5):631-8
pubmed: 22019723
Am J Pathol. 2008 Feb;172(2):521-33
pubmed: 18187566