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The Role of Activator Protein-1 in Sepsis-Associated Encephalopathy: Inhibition of Microglial Activation via Transcriptional Regulation of Cold-Inducible RNA-Binding Protein
Vol 38, Issue 4, 2024
Abstract
Background: Cold-inducible RNA-binding protein (CIRP) promotes inflammatory responses. Activator protein-1 (AP-1) potentially acts as a transcriptional regulator of CIRP. Consequently, this study aims to investigate the impact of the AP-1-CIRP axis on microglial activation to mitigate neural injury in sepsis-associated encephalopathy (SAE). Methods: We employed a Streptococcus pneumoniae-induced mouse SAE model in vivo and lipopolysaccharide (LPS)-induced BV-2 cells for in vitro experiments. The spatial exploration ability of mice was assessed using the Morris water maze assay. Levels of inflammatory factors were determined via enzyme-linked immunosorbent assay. Microglial activation in the cerebral cortex and hippocampus was determined through immunohistochemistry or immunofluorescence. Degenerated neurons were identified using Fluoro-Jade C staining. Quantifications of mRNA and protein levels in tissues, cells, and supernatants were conducted through real-time quantitative polymerase chain reaction and Western blot, respectively. The binding relationship between AP-1 and CIRP was analyzed using JASPAR and chromatin immunoprecipitation. Reactive oxygen species (ROS) levels were measured via 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) assay. Results: Silencing of AP-1 led to reduced levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β levels, as well as a decrease in Iba1+ cells in SAE mice. Cognitive impairment and neuronal degeneration in the brains of SAE mice were partially alleviated by AP-1 silencing. Furthermore, elevated levels of FOS Like 1 (Fosl1), JunB Proto-Oncogene (Junb), Jun Proto-Oncogene (Jun), and CIRP in SAE mice were partially attenuated by AP-1 silencing. We observed that AP-1 is bound to the CIRP promoter region. Inhibition of AP-1 or CIRP reduced levels of inflammatory factors, CD11b+ cells, ROS, pro-apoptosis-related protein, and extracellular CIRP. Conversely, AP-1 overexpression exhibited the opposite effects reversed by CIRP silencing in LPS-induced cells. Conclusion: Inhibition of AP-1 ameliorates neuronal injury in SAE by suppressing microglial activation through transcriptional regulation of CIRP.
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Copyright (c) 2024 Xinxin Li, Wei Zhou, Liangliang Zhou, Yingbin Li, Xufeng Wu, Jianjun Chen
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Medical Genetics, University of Torino Medical School, Italy

Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy