Upon pathogen infection, the host innate immune system is excessively activated innate immune activation is followed by and causes the occurrence of a cytokine storm, which is characterized by high levels of pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, and IFN-γ, and results in cell death and multiple organ dysfunction. Sepsis is a common complication after infection, shock and severe trauma, and it is one of the major causes of mortality in patients in intensive care units (ICUs). In summary, our findings demonstrate for the first time that S100A9 plays an important pro-inflammatory role in sepsis-mediated ALI by regulating AKT-AMPK-dependent mitochondrial energy metabolism and highlights that targeting S100A9 may be a promising new approach for the prevention and treatment of sepsis-related liver injury. Finally, the administration of the S100A9 inhibitor Paquinimod (Paq) to WT mice protected against CLP-induced mortality, liver injury and mitochondrial dysfunction. In contrast, treatment with the AMPK inhibitor Compound C reversed the inhibitory effects of S100A9 KO on CLP-induced liver dysfunction and injury in vivo. Moreover, S100A9-KO in mice markedly attenuated CLP-induced liver dysfunction and injury, promoting the AMPK/ACC/GLUT4-mediated increases in fatty acid and glucose uptake as well as the improvement in mitochondrial function and ATP production. Our results indicated that S100A8/A9 expression was significantly upregulated in the livers of septic mice 24 h after cecal ligation and a puncture (CLP) operation. However, the role of S100A8/A9 in the regulation of sepsis-induced ALI remains known. S100A8/A9 is known to promote inflammation and immune responses. Acute liver injury (ALI) is recognized as a serious complication of sepsis in patients in intensive care units (ICUs).
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