The role and mechanism of the NLRP3-IL-1β/IL-18 signaling axis in the progression of sepsis under an aging phenotype

AIMS: To investigate the impact of age on sepsis outcomes and explore potential therapeutic targets using the mouse model. MATERIALS AND METHODS: Sepsis was induced via cecal ligation and puncture (CLP) in naturally aged mice (18 months) and young mice (3 months). Sepsis severity, mortality rates, bacterial loads, and cytokine levels (IL-18 and IL-1β) were compared between the two groups. NLRP3 expression was analyzed in various organs. Additionally, NLRP3 inhibitor MCC950 and specific antibodies against IL-18 and IL-1β were administered to assess their therapeutic effects. Note: This study was partially based on human samples. KEY FINDINGS: Aged mice demonstrated more severe sepsis symptoms and increased mortality compared to young mice. Elevated levels of IL-18 and IL-1β were observed in aged septic mice, indicative of augmented NLRP3 inflammasome activation. Human data corroborated these findings, showing higher serum levels of IL-18 and IL-1β in older sepsis patients. Treatment with NLRP3 inhibition (MCC950) and antibodies against IL-18 and IL-1β alleviated sepsis symptoms in aged mice, suggesting these pathways as potential therapeutic targets. SIGNIFICANCE: The study highlights the critical role of the NLRP3-IL-18/IL-1β axis in age-related disparities in sepsis outcomes and suggests potential therapeutic targets for improving outcomes in aged sepsis patients.