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Targeting gliovascular connexins prevents inflammatory blood-brain barrier leakage and astrogliosis

Marijke De Bock (UGent) , Maarten De Smet, Stijn Verwaerde (UGent) , Hanane Tahiri (UGent) , Steffi Schumacher (UGent) , Valérie Van Haver, Katja Witschas (UGent) , Christian Steinhäuser, Nathalie Rouach, Roosmarijn Vandenbroucke (UGent) , et al.
(2022) JCI INSIGHT. 7(16).
Author
Organization
Abstract
The blood-brain barrier is formed by capillary endothelial cells expressing connexin 37 (Cx37), Cx40, and Cx43 and is joined by closely apposed astrocytes expressing Cx43 and Cx30. We investigated whether connexin-targeting peptides could limit barrier leakage triggered by LPS-induced systemic inflammation in mice. Intraperitoneal LPS administration increased endothelial and astrocytic Cx43 expression; elevated TNF-alpha, IL-1 beta, IFN-gamma, and IL-6 in plasma and IL-6 in the brain; and induced barrier leakage recorded over 24 hours. Barrier leakage was largely prevented by global Cx43 knockdown and Cx43/Cx30 double knockout in astrocytes, slightly diminished by endothelial Cx43 knockout, and not protected by global Cx30 knockout. Intravenous administration of Gap27 or Tat-Gap19 peptides just before LPS also prevented barrier leakage, and intravenously administered BAPTA-AM to chelate intracellular calcium was equally effective. Patch-clamp experiments demonstrated LPS-induced Cx43 hemichannel opening in endothelial cells, which was suppressed by Gap27, Gap19, and BAPTA. LPS additionally triggered astrogliosis that was prevented by intravenous Tat-Gap19 or BAPTA-AM. Cortically applied Tat-Gap19 or BAPTA-AM to primarily target astrocytes also strongly diminished barrier leakage. In vivo dye uptake and in vitro patch-clamp showed Cx43 hemichannel opening in astrocytes that was induced by IL-6 in a calcium-dependent manner. We conclude that targeting endothelial and astrocytic connexins is a powerful approach to limit barrier failure and astrogliosis.
Keywords
General Medicine, ENDOTHELIAL CALCIUM DYNAMICS, CX43 HEMICHANNELS, NEUROVASCULAR UNIT, MIMETIC PEPTIDE, CELL-DEATH, IN-VIVO, ASTROCYTES, CA2+, HEALTH, GFAP

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Citation

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MLA
De Bock, Marijke, et al. “Targeting Gliovascular Connexins Prevents Inflammatory Blood-Brain Barrier Leakage and Astrogliosis.” JCI INSIGHT, vol. 7, no. 16, 2022, doi:10.1172/jci.insight.135263.
APA
De Bock, M., De Smet, M., Verwaerde, S., Tahiri, H., Schumacher, S., Van Haver, V., … Leybaert, L. (2022). Targeting gliovascular connexins prevents inflammatory blood-brain barrier leakage and astrogliosis. JCI INSIGHT, 7(16). https://doi.org/10.1172/jci.insight.135263
Chicago author-date
De Bock, Marijke, Maarten De Smet, Stijn Verwaerde, Hanane Tahiri, Steffi Schumacher, Valérie Van Haver, Katja Witschas, et al. 2022. “Targeting Gliovascular Connexins Prevents Inflammatory Blood-Brain Barrier Leakage and Astrogliosis.” JCI INSIGHT 7 (16). https://doi.org/10.1172/jci.insight.135263.
Chicago author-date (all authors)
De Bock, Marijke, Maarten De Smet, Stijn Verwaerde, Hanane Tahiri, Steffi Schumacher, Valérie Van Haver, Katja Witschas, Christian Steinhäuser, Nathalie Rouach, Roosmarijn Vandenbroucke, and Luc Leybaert. 2022. “Targeting Gliovascular Connexins Prevents Inflammatory Blood-Brain Barrier Leakage and Astrogliosis.” JCI INSIGHT 7 (16). doi:10.1172/jci.insight.135263.
Vancouver
1.
De Bock M, De Smet M, Verwaerde S, Tahiri H, Schumacher S, Van Haver V, et al. Targeting gliovascular connexins prevents inflammatory blood-brain barrier leakage and astrogliosis. JCI INSIGHT. 2022;7(16).
IEEE
[1]
M. De Bock et al., “Targeting gliovascular connexins prevents inflammatory blood-brain barrier leakage and astrogliosis,” JCI INSIGHT, vol. 7, no. 16, 2022.
@article{8763075,
  abstract     = {{The blood-brain barrier is formed by capillary endothelial cells expressing connexin 37 (Cx37), Cx40, and Cx43 and is joined by closely apposed astrocytes expressing Cx43 and Cx30. We investigated whether connexin-targeting peptides could limit barrier leakage triggered by LPS-induced systemic inflammation in mice. Intraperitoneal LPS administration increased endothelial and astrocytic Cx43 expression; elevated TNF-alpha, IL-1 beta, IFN-gamma, and IL-6 in plasma and IL-6 in the brain; and induced barrier leakage recorded over 24 hours. Barrier leakage was largely prevented by global Cx43 knockdown and Cx43/Cx30 double knockout in astrocytes, slightly diminished by endothelial Cx43 knockout, and not protected by global Cx30 knockout. Intravenous administration of Gap27 or Tat-Gap19 peptides just before LPS also prevented barrier leakage, and intravenously administered BAPTA-AM to chelate intracellular calcium was equally effective. Patch-clamp experiments demonstrated LPS-induced Cx43 hemichannel opening in endothelial cells, which was suppressed by Gap27, Gap19, and BAPTA. LPS additionally triggered astrogliosis that was prevented by intravenous Tat-Gap19 or BAPTA-AM. Cortically applied Tat-Gap19 or BAPTA-AM to primarily target astrocytes also strongly diminished barrier leakage. In vivo dye uptake and in vitro patch-clamp showed Cx43 hemichannel opening in astrocytes that was induced by IL-6 in a calcium-dependent manner. We conclude that targeting endothelial and astrocytic connexins is a powerful approach to limit barrier failure and astrogliosis.}},
  articleno    = {{e135263}},
  author       = {{De Bock, Marijke and De Smet, Maarten and Verwaerde, Stijn and Tahiri, Hanane and Schumacher, Steffi and Van Haver, Valérie and Witschas, Katja and Steinhäuser, Christian and Rouach, Nathalie and Vandenbroucke, Roosmarijn and Leybaert, Luc}},
  issn         = {{2379-3708}},
  journal      = {{JCI INSIGHT}},
  keywords     = {{General Medicine,ENDOTHELIAL CALCIUM DYNAMICS,CX43 HEMICHANNELS,NEUROVASCULAR UNIT,MIMETIC PEPTIDE,CELL-DEATH,IN-VIVO,ASTROCYTES,CA2+,HEALTH,GFAP}},
  language     = {{eng}},
  number       = {{16}},
  pages        = {{19}},
  title        = {{Targeting gliovascular connexins prevents inflammatory blood-brain barrier leakage and astrogliosis}},
  url          = {{http://doi.org/10.1172/jci.insight.135263}},
  volume       = {{7}},
  year         = {{2022}},
}
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