Astrocytic Slc4a4 regulates blood-brain barrier integrity in healthy and stroke brains via a CCL2-CCR2 pathway and NO dysregulation

Qi Ye; Juyeon Jo; Chih-Yen Wang; Heavin Oh; Jiangshan Zhan; Tiffany J. Choy; Kyoung In Kim; Angelo D’Alessandro; Yana K. Reshetnyak; Sung Yun Jung; Zheng Chen; Sean P. Marrelli; Hyun Kyoung Lee

Cell Reports (May 2024)

Astrocytic Slc4a4 regulates blood-brain barrier integrity in healthy and stroke brains via a CCL2-CCR2 pathway and NO dysregulation

Qi Ye,
Juyeon Jo,
Chih-Yen Wang,
Heavin Oh,
Jiangshan Zhan,
Tiffany J. Choy,
Kyoung In Kim,
Angelo D’Alessandro,
Yana K. Reshetnyak,
Sung Yun Jung,
Zheng Chen,
Sean P. Marrelli,
Hyun Kyoung Lee

Affiliations

Qi Ye: Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
Juyeon Jo: Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
Chih-Yen Wang: Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan 70101, Taiwan
Heavin Oh: Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
Jiangshan Zhan: Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
Tiffany J. Choy: Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; Cancer and Cell Biology Program, Baylor College of Medicine, Houston, TX 77030, USA
Kyoung In Kim: Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
Angelo D’Alessandro: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 77030, USA
Yana K. Reshetnyak: Physics Department, University of Rhode Island, Kingston, RI 02881, USA
Sung Yun Jung: Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA
Zheng Chen: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Sean P. Marrelli: Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Hyun Kyoung Lee: Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; Cancer and Cell Biology Program, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Corresponding author

Journal volume & issue: Vol. 43, no. 5
p. 114193

Abstract

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Summary: Astrocytes play vital roles in blood-brain barrier (BBB) maintenance, yet how they support BBB integrity under normal or pathological conditions remains poorly defined. Recent evidence suggests that ion homeostasis is a cellular mechanism important for BBB integrity. In the current study, we investigated the function of an astrocyte-specific pH regulator, Slc4a4, in BBB maintenance and repair. We show that astrocytic Slc4a4 is required for normal astrocyte morphological complexity and BBB function. Multi-omics analyses identified increased astrocytic secretion of CCL2 coupled with dysregulated arginine-NO metabolism after Slc4a4 deletion. Using a model of ischemic stroke, we found that loss of Slc4a4 exacerbates BBB disruption, which was rescued by pharmacological or genetic inhibition of the CCL2-CCR2 pathway in vivo. Together, our study identifies the astrocytic Slc4a4-CCL2 and endothelial CCR2 axis as a mechanism controlling BBB integrity and repair, while providing insights for a therapeutic approach against BBB-related CNS disorders.

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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