Astrocytic Slc4a4 Regulates Blood-Brain Barrier Integrity in Healthy and Stroke Brains via a CCL2-CCR2 Pathway and No Dysregulation

Authors

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

Publication Date

5-28-2024

Journal

Cell Reports

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

Animals, Humans, Male, Mice, Astrocytes, Blood-Brain Barrier, Brain, Chemokine CCL2, Mice, Inbred C57BL, Receptors, CCR2, Signal Transduction, Stroke, Sodium-Bicarbonate Symporters

Comments

Supplementary Materials

Data Availability Statement

PMID: 38709635