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

Ye, Q.; Jo, J.; Wang, C.-Y.; Oh, H.; Choy, T.; Kim, K.; D'Alessandro, A.; Reshetnyak, Y. K.; Jung, S. Y.; Chen, Z.; Marrelli, S. P.; Lee, H. K.

doi:10.1101/2023.04.03.535167

bioRxiv · 10.1101/2023.04.03.535167

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

Ye, Q.·Jo, J.·Wang, C.-Y.·Oh, H.·Choy, T.·Kim, K.·D'Alessandro, A.·Reshetnyak, Y. K.·Jung, S. Y.·Chen, Z.·Marrelli, S. P.·Lee, H. K.

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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 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.

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Ye, Q., Jo, J., Wang, C.-Y., Oh, H., Choy, T., Kim, K., D'Alessandro, A., Reshetnyak, Y. K., Jung, S. Y., Chen, Z., Marrelli, S. P., Lee, H. K.. 2023-04-03. Astrocytic Slc4a4 regulates blood-brain barrier integrity in healthy and stroke brains via a NO-CCL2-CCR2 pathway. https://doi.org/10.1101/2023.04.03.535167

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