Astrocytic Slc4a4 Regulates Blood-brain Barrier Integrity in Healthy and Stroke Brains Via a CCL2-CCR2 Pathway and NO Dysregulation

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2024 May 6

PMID 38709635

Authors

Qi Ye

Juyeon Jo

Chih-Yen Wang

Heavin Oh

Jiangshan Zhan

Tiffany J Choy

Kyoung In Kim

Angelo DAlessandro

Yana K Reshetnyak

Sung Yun Jung

Zheng Chen

Sean P Marrelli

Hyun Kyoung Lee

Affiliations

Soon will be listed here.

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.

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