Abstract
Blood-brain barrier (BBB) integrity is crucial for maintaining the function and environmental homeostasis of the central nervous system (CNS). Astrocytes play a critical role in the constitution of the BBB. In this study, we found that Japanese encephalitis virus (JEV) infection causes HMGB1 to translocate and release from the nucleus to the extracellular space in astrocytes, as well as elevated HMGB1 levels in the brain, which is related to BBB breakdown. Mechanistically, extracellular HMGB1 induces Ca2+ influx into astrocytes, leading to the overexpression of calmodulin (CaM) and the water channel protein aquaporin-4 (AQP4), triggering the phosphorylation of calmodulin kinase II (CaMKII) and promoting the translocation of AQP4 from the cytoplasm to the cell membrane. Inhibition of CaM, CaMKII, and AQP4 could block the cell membrane translocation of AQP4, thereby alleviating HMGB1-mediated BBB disruption. Extracellular HMGB1 is considered a potential target for mitigating neuroinflammation and BBB disruption. The positive feedback loop of HMGB1 exacerbates the disturbance of the BBB. These findings indicate that the HMGB1-AQP4 axis plays a role in the regulation of BBB integrity, presenting a new therapeutic target for the clinical treatment of JE and other CNS illnesses.