This study investigates the role of interleukin-22 (IL-22) in blood-brain barrier (BBB) disruption caused by Escherichia coli meningitis. IL-22, a cytokine belonging to the interleukin-10 family, was found to be significantly upregulated in the serum and brain of mice infected with meningitic E. coli. The study demonstrates that IL-22 contributes to BBB disruption by activating the STAT3/VEGFA signaling pathway, leading to the degradation of tight junction proteins (TJPs) such as ZO-1, Occludin, and Claudin-5. These TJPs are critical for maintaining BBB integrity, and their degradation results in increased BBB permeability and disruption of the barrier function. The study used in vitro and in vivo models to show that IL-22 treatment reduced TEER (trans-endothelial electrical resistance) in human brain microvascular endothelial cells (hBMEC), indicating impaired BBB function. Additionally, IL-22 treatment increased the permeability of the BBB in mice, as evidenced by increased Evans blue dye leakage. Knockout of IL-22 in mice significantly reduced BBB permeability, suggesting that IL-22 is a key contributor to BBB disruption in E. coli meningitis. Mechanistically, IL-22 activates STAT3, which in turn upregulates VEGFA expression. VEGFA is a key factor in BBB permeability and is involved in the pathogenesis of BBB disruption. The study also shows that VEGFA expression is dependent on STAT3 activation, and that blocking STAT3 activity reduces IL-22-induced BBB disruption. Furthermore, the study demonstrates that VEGFA is essential for IL-22-induced BBB damage, as VEGFA knockout in hBMEC significantly reduced BBB permeability and TJP degradation. These findings suggest that IL-22 plays a critical role in BBB disruption during E. coli meningitis by activating the STAT3/VEGFA pathway. Targeting IL-22 could be a promising therapeutic strategy for preventing and treating bacterial meningitis by maintaining BBB integrity. The study highlights the importance of understanding the role of IL-22 in BBB dysfunction and provides new insights into the pathogenesis of E. coli meningitis.This study investigates the role of interleukin-22 (IL-22) in blood-brain barrier (BBB) disruption caused by Escherichia coli meningitis. IL-22, a cytokine belonging to the interleukin-10 family, was found to be significantly upregulated in the serum and brain of mice infected with meningitic E. coli. The study demonstrates that IL-22 contributes to BBB disruption by activating the STAT3/VEGFA signaling pathway, leading to the degradation of tight junction proteins (TJPs) such as ZO-1, Occludin, and Claudin-5. These TJPs are critical for maintaining BBB integrity, and their degradation results in increased BBB permeability and disruption of the barrier function. The study used in vitro and in vivo models to show that IL-22 treatment reduced TEER (trans-endothelial electrical resistance) in human brain microvascular endothelial cells (hBMEC), indicating impaired BBB function. Additionally, IL-22 treatment increased the permeability of the BBB in mice, as evidenced by increased Evans blue dye leakage. Knockout of IL-22 in mice significantly reduced BBB permeability, suggesting that IL-22 is a key contributor to BBB disruption in E. coli meningitis. Mechanistically, IL-22 activates STAT3, which in turn upregulates VEGFA expression. VEGFA is a key factor in BBB permeability and is involved in the pathogenesis of BBB disruption. The study also shows that VEGFA expression is dependent on STAT3 activation, and that blocking STAT3 activity reduces IL-22-induced BBB disruption. Furthermore, the study demonstrates that VEGFA is essential for IL-22-induced BBB damage, as VEGFA knockout in hBMEC significantly reduced BBB permeability and TJP degradation. These findings suggest that IL-22 plays a critical role in BBB disruption during E. coli meningitis by activating the STAT3/VEGFA pathway. Targeting IL-22 could be a promising therapeutic strategy for preventing and treating bacterial meningitis by maintaining BBB integrity. The study highlights the importance of understanding the role of IL-22 in BBB dysfunction and provides new insights into the pathogenesis of E. coli meningitis.