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

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

  • Life Sci. 2025 Jun 16:123812. doi: 10.1016/j.lfs.2025.123812.
Chuchu Xu 1,  Renjun Zhu 2,  Qingfeng Dai 3,  Guangen Xu 4,  Guolin Zhang 5
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang Province, China. Electronic address: chuchuxu@zju.edu.cn.
  • 2 Department of Emergency, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang Province, China.
  • 3 Zhijiang College, Zhejiang University of Technology, Shaoxing 312000, Zhejiang Province, China.
  • 4 Department of Gastrointestinal Surgery, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang Province, China.
  • 5 Department of Gastrointestinal Surgery, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang Province, China. Electronic address: zhangguolin@zju.edu.cn.
PMID: 40532971 DOI: 10.1016/j.lfs.2025.123812
Abstract

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.

Keywords

Aging; CLP model; IL-18; IL-1β; NLRP3; Sepsis.

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