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

Abstract

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 Foxc1 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-κB (IκΒα) whilst increasing that of p65, IL-1β and TNF-α. After Foxc1 was overexpressed, the cognitive dysfunction of mice that underwent CLP surgery was improved, with the expression of IκBα also increased, microglial cell migration, the expression of p65, IL-1β and TNF-α and neuronal apoptosis were all decreased in vivo and in vitro , which were in turn reversed by the inhibition of IκBα 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 IκBα/NF-κB pathway, thereby improving cognitive dysfunction during SAE.

Identification of novel prognostic targets in acute kidney injury using bioinformatics and next generation sequencing data analysis

“…E2F1 [433], VCAM1 [485], AGTR1 [71], hsa-mir-221 [801], MEF2A [802] and YY1 [803] are associated with developing liver diseases. E2F1 [496], AGTR1 [74], VCAM1 [533], hsa-mir-7847-3p [804], FOXC1 [805], USF2 [796], YY1 [806], STAT3 [807] and BRCA1 [799] have been observed in sepsis patients. Studies have shown that E2F1 [669], VCAM1 [715], AGTR1 [83], hsa-mir-221 [780], YY1 [808], STAT3 [809], PDX1 [810] and BRCA1 [811] are associated with obesity.…”

IL-1β, the first piece to the puzzle of sepsis-related cognitive impairment?

“…The nuclear factor kappa B (NF-κB) signaling pathway is a key signal pathway that modulates inflammatory responses. Studies have shown that the NF-κB signaling pathway is involved in the activation of microglia during sepsis ( Mulero et al, 2019 ; Zhao et al, 2019 ; Nguyen et al, 2021 ; Wang H. et al, 2022 ). The NF-κB family consists of subunits p105/p50, p100/p52, p65/RelA, RelB, and c-Rel.…”

Role of Microglia in Sepsis-Associated Encephalopathy Pathogenesis: An Update

“…Excessive microglial activation has been proposed as a significant factor for cognitive dysfunction underlying SAE (48). Recent studies have demonstrated that reducing microglia hyperactivation or altering the microglial phenotype can enhance neuroinflammation and cognitive dysfunction in SAE (49,50). Microglial overactivation predominantly results in the abundance of the M1 phenotype, which has been identified as an important factor in the development of cognitive dysfunction and neuroinflammation in SAE (30).…”

“…Microglial migration is associated with classical inflammatory signaling pathways, including NF-κB and JAK-STAT. Inhibiting these pathways effectively suppresses both microglia activation and migration, along with neuroinflammatory responses (49,64). Granulocyte colony-stimulating factor and CCL11 induce ROS production through the promotion of microglial migration to inflamed areas, further leading to neuronal damage (65).…”

“…Furthermore, the NF-κB pathway plays a crucial role in regulating microglial migration. Inhibition of the NF-κB pathway using Forkhead box C1 effectively suppresses microglial migration, causing the attenuation of neuroinflammatory responses and neuronal apoptosis in the brain tissue, ultimately resulting in the improvement of cognitive dysfunction in SAE (49). The NF-κB pathway may activate microglia and promote their proinflammatory effects by creating an inflammatory environment, polarizing microglial cells, and facilitating their migration into the brain.…”