S100A8/A9 Inhibition Reduces Neutrophil Extracellular Trap Formation and Mitigates Sepsis-Related Liver Injury.

PURPOSE: Sepsis is a leading cause of death in patients admitted to the intensive care unit. Sepsis-related liver injury (SRLI) is a fatal complication of sepsis with limited early diagnostic and therapeutic options. We investigated the role of the damage-associated molecular patterns S100A8/A9 in SRLI pathogenesis, with particular focus on their interaction with neutrophil extracellular traps (NETs).

PATIENTS AND

METHODS

Bioinformatics analysis of sepsis datasets from the Gene Expression Omnibus database was integrated with clinical validation using an enzyme-linked immunosorbent assay with patient plasma. The functional role of S100A8/A9 was further explored in a murine cecal ligation and puncture (CLP) sepsis model. Mice were pretreated with the S100A8/A9 inhibitor paquinimod to assess its effects on NET formation (via immunofluorescence and Western blotting), liver injury (serum alanine aminotransferase and aspartate aminotransferase levels and histopathology), inflammatory response (cytokine levels), and survival rates.

RESULTS

Bioinformatics analysis identified S100A8/A9 as a key hub gene in sepsis. Clinically, plasma S100A8/A9 levels were significantly elevated in patients with sepsis, particularly in those with liver injury. In CLP mice, hepatic S100A8/A9 was upregulated, and paquinimod-induced inhibition of S100A8/A9 markedly reduced NET formation, lowered interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha levels, alleviated liver damage, and improved survival rates. Transcriptome sequencing revealed alterations in immune and metabolic pathways.

CONCLUSION

This study suggests that elevated S100A8/A9 and concurrent NETosis are closely associated with sepsis-related liver injury (SRLI). S100A8/A9 can be used as a potential predictive biomarker for early liver dysfunction, and prophylactic administration of paquinimod can reduce intrahepatic inflammation, reduce NET formation, and improve the survival rate of mice with sepsis.