Overexpression of Foxc1 ameliorates sepsis-associated encephalopathy by inhibiting microglial migration and neuroinflammation through the IκBα/NF-κB pathway

Sepsis-associated encephalopathy (SAE) is a common and severe complication of sepsis. The cognitive dysfunction that ensues during SAE has been reported to be caused by impairments of the hippocampus. Microglia serves a key role in neuroinflammation during SAE through migration. Forkhead box C1 (Foxc1) is a member of the forkhead transcription factor family that has been found to regulate in cell migration. However, the role of Foxc1 in neuroinflammation during SAE remains unknown. In the present study, the mechanistic role of Foxcl on microglial migration, neuroinflammation and neuronal apoptosis during the occurrence of cognitive dysfunction in SAE was investigated. A microglia-mediated inflammation model was induced by LPS in BV-2 microglial cells in vitro, whilst a SAE-related cognitive impairment model was established in mice using cecal ligation and perforation (CLP) surgery. Cognitive function in mice was evaluated using the Morris Water Maze (MWM) trial. Lipopolysaccharide (LPS) treatment was found to trigger BV-2 cell migration, inflammation and neuronal apoptosis. In addition, CLP surgery induced cognitive injury, which was indicated by longer latencies and shorter dwell times in the goal quadrant compared with those in the Sham group in the MWM trial. LPS treatment or CLP induction decreased the expression of Foxc1 and inhibitor of NF-kappa B (I kappa B alpha) whilst increasing that of p65, IL-1 beta and TNF-alpha. After Foxc1 was overexpressed, the cognitive dysfunction of mice that underwent CLP surgery was improved, with the expression of I kappa B alpha also increased, microglial cell migration, the expression of p65, IL-1 beta and TNF-alpha and neuronal apoptosis were all decreased in vivo and in vitro, which were in turn reversed by the inhibition of I kappa B alpha in vitro. Overall, these results suggest that the overexpression of Foxc1 inhibited microglial migration whilst suppressing the inflammatory response and neuronal apoptosis by regulating the I kappa B alpha/NF-kappa B pathway, thereby improving cognitive dysfunction during SAE.

Automated summary

Sepsis-associated encephalopathy (SAE) is a common and severe complication of sepsis, leading to cognitive dysfunction. This study found that overexpression of Foxc1 inhibited microglial migration and reduced inflammatory response and neuronal apoptosis through regulation of the IκBα/NF-κB pathway, thereby improving cognitive dysfunction during SAE.