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
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.
