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

Autor:	Ye Q; Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX, USA.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA., Jo J; Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX, USA.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA., Wang CY; Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX, USA.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA., Oh H; Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX, USA.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA., Choy TJ; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.; Cancer and Cell Biology Program, Baylor College of Medicine, Houston, TX, USA., Kim K; Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX, USA.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA., D'Alessandro A; Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA., Reshetnyak YK; Physics Department, University of Rhode Island, Kingston, RI, USA., Jung SY; Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA., Chen Z; Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX, USA., Marrelli SP; Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA., Lee HK; Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX, USA.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Apr 03. Date of Electronic Publication: 2023 Apr 03.
DOI:	10.1101/2023.04.03.535167
Abstrakt:	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 pH homeostasis is a new 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 and reactive gliosis, which were both rescued by pharmacological or genetic inhibition of the NO-CCL2 pathway in vivo. Together, our study identifies the astrocytic Slc4a4-NO-CCL2 axis as a pivotal mechanism controlling BBB integrity and repair, while providing insights for a novel therapeutic approach against BBB-related CNS disorders. Competing Interests: Conflicts of interests Y.K.R. is the founder of pHLIP Inc., but the company did not fund any part of the work reported here. The authors declare no other competing interests.
Databáze:	MEDLINE
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