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Distinct roles of A1/A2 astrocytes in blood-brain barrier injury following cerebral I/R via the ROCK/NF-κB and STAT3 pathways

Zhifeng Geng,Guoyi Deng,Ziyu Wang,Xin Xu,Xiaojiao Yin,Sen Zhang,Jiale Shao,Jiyue Wen

Astrocytes may fail to perform their neuroprotective roles against cerebral ischemia/reperfusion (I/R) injury due to phenotypic transformation. We aimed to demonstrate the distinct roles of A1 astrocytes and A2 astrocytes on the blood-brain barrier (BBB) injury following cerebral I/R, and explore whether H 2 S-mediated A2 astrocytes polarization protects against BBB injury via inhibiting ROCK/NF-κB pathway. The mice cerebral I/R model and the oxygen-glucose deprivation/re‑oxygenation (OGD/R) model of astrocytes were used in present study. Cerebral I/R-induced BBB injury is evidenced by increased EB dye leakage and reduced expressions of ZO-1 and occludin in mice hippocampal tissues. We found that H 2 S-mediated A2 polarization and lipopolysaccharide (LPS)-induced polarization of A1 astrocytes respectively display beneficial and harmful role in BBB injury. Besides, harmful roles of A1 astrocytes in BBB injury can be reduced by H 2 S. Additionally, A1 astrocytes exhibit excessive activation of NF-κB and enhanced expressions of MMP9 and AQP4, which can be inhibited by H 2 S. Moreover, H 2 S-mediated polarization of A2 astrocyte displays enhanced phosphorylation and nuclear translocation of STAT3 and reduced expressions of MMP9 and AQP4. Importantly, ROCK inhibitor Fasudil likewise inhibits the activation of NF-κB and promotes STAT3 activation in OGD/R astrocytes, and NF-κB inhibitor BAY11–7082 reduces the expressions of MMP9 and AQP4 in OGD/R astrocytes. In conclusion, H 2 S-mediated polarization of A2 astrocyte protects against BBB injury following cerebral I/R, the mechanisms may be related to inhibition of ROCK/NF-κB pathway, and activation of STAT3.