This study investigates the role of interleukin-22 (IL-22) in the disruption of the blood-brain barrier (BBB) during Escherichia coli meningitis. The authors found that IL-22 expression was significantly increased in the serum and brain of mice infected with meningitic E. coli. IL-22 administration led to the degradation of tight junction proteins (TJPs) such as ZO-1, Occludin, and Claudin-5 in human brain microvascular endothelial cells (hBMEC), resulting in decreased transendothelial electrical resistance (TEER) and increased BBB permeability. The disruption of the BBB by IL-22 was found to be mediated through the activation of the STAT3-VEGFA signaling pathway. Specifically, IL-22 activated STAT3, which in turn upregulated VEGFA expression, leading to the degradation of TJPs. Knocking out IL-22 in mice or inhibiting STAT3 activity using a specific inhibitor reduced the disruption of the BBB by meningitic E. coli. These findings suggest that IL-22 is a critical host factor in the BBB disruption during E. coli meningitis and could be a potential therapeutic target for bacterial meningitis.This study investigates the role of interleukin-22 (IL-22) in the disruption of the blood-brain barrier (BBB) during Escherichia coli meningitis. The authors found that IL-22 expression was significantly increased in the serum and brain of mice infected with meningitic E. coli. IL-22 administration led to the degradation of tight junction proteins (TJPs) such as ZO-1, Occludin, and Claudin-5 in human brain microvascular endothelial cells (hBMEC), resulting in decreased transendothelial electrical resistance (TEER) and increased BBB permeability. The disruption of the BBB by IL-22 was found to be mediated through the activation of the STAT3-VEGFA signaling pathway. Specifically, IL-22 activated STAT3, which in turn upregulated VEGFA expression, leading to the degradation of TJPs. Knocking out IL-22 in mice or inhibiting STAT3 activity using a specific inhibitor reduced the disruption of the BBB by meningitic E. coli. These findings suggest that IL-22 is a critical host factor in the BBB disruption during E. coli meningitis and could be a potential therapeutic target for bacterial meningitis.