Mosaic deletion of claudin-5 reveals rapid non-cell-autonomous consequences of blood-brain barrier leakage

Elisa Vázquez-Liébanas; Giuseppe Mocci; Weihan Li; Bàrbara Laviña; Avril Reddy; Claire O’Connor; Natalie Hudson; Zaher Elbeck; Ioannis Nikoloudis; Konstantin Gaengel; Michael Vanlandewijck; Matthew Campbell; Christer Betsholtz; Maarja Andaloussi Mäe

Cell Reports (Mar 2024)

Mosaic deletion of claudin-5 reveals rapid non-cell-autonomous consequences of blood-brain barrier leakage

Elisa Vázquez-Liébanas,
Giuseppe Mocci,
Weihan Li,
Bàrbara Laviña,
Avril Reddy,
Claire O’Connor,
Natalie Hudson,
Zaher Elbeck,
Ioannis Nikoloudis,
Konstantin Gaengel,
Michael Vanlandewijck,
Matthew Campbell,
Christer Betsholtz,
Maarja Andaloussi Mäe

Affiliations

Elisa Vázquez-Liébanas: Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden
Giuseppe Mocci: Single Cell Core Facility of Flemingsberg Campus (SICOF), Karolinska Institute, 14157 Huddinge, Sweden
Weihan Li: Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden
Bàrbara Laviña: Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden
Avril Reddy: Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
Claire O’Connor: Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
Natalie Hudson: Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
Zaher Elbeck: Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden
Ioannis Nikoloudis: Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden
Konstantin Gaengel: Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden
Michael Vanlandewijck: Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden; Single Cell Core Facility of Flemingsberg Campus (SICOF), Karolinska Institute, 14157 Huddinge, Sweden; Department of Medicine, Karolinska Institute, 14157 Huddinge, Sweden
Matthew Campbell: Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
Christer Betsholtz: Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden; Department of Medicine, Karolinska Institute, 14157 Huddinge, Sweden
Maarja Andaloussi Mäe: Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden; Corresponding author

Journal volume & issue: Vol. 43, no. 3
p. 113911

Abstract

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Summary: Claudin-5 (CLDN5) is an endothelial tight junction protein essential for blood-brain barrier (BBB) formation. Abnormal CLDN5 expression is common in brain disease, and knockdown of Cldn5 at the BBB has been proposed to facilitate drug delivery to the brain. To study the consequences of CLDN5 loss in the mature brain, we induced mosaic endothelial-specific Cldn5 gene ablation in adult mice (Cldn5iECKO). These mice displayed increased BBB permeability to tracers up to 10 kDa in size from 6 days post induction (dpi) and ensuing lethality from 10 dpi. Single-cell RNA sequencing at 11 dpi revealed profound transcriptomic differences in brain endothelial cells regardless of their Cldn5 status in mosaic mice, suggesting major non-cell-autonomous responses. Reactive microglia and astrocytes suggested rapid cellular responses to BBB leakage. Our study demonstrates a critical role for CLDN5 in the adult BBB and provides molecular insight into the consequences and risks associated with CLDN5 inhibition.

CP: Neuroscience

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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