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

doi:10.1016/j.celrep.2024.114193

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

Cell Rep. 2024 May 5;43(5):114193. doi: 10.1016/j.celrep.2024.114193. Online ahead of print.

Authors

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 77030, USA.
⁵ Physics Department, University of Rhode Island, Kingston, RI 02881, USA.
⁶ Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁸ Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁹ 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. Electronic address: hyunkyol@bcm.edu.

PMID: 38709635
DOI: 10.1016/j.celrep.2024.114193

Abstract

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.

Keywords: CCL2-CCR2; CP: Neuroscience; Slc4a4; arginine; astrocyte; blood-brain barrier; caveolin; endothelia; ischemic stroke; nitric oxide; pH regulation.