Neutralization of IL-33 ameliorates septic myocardial injury through anti-inflammatory, anti-oxidative, and anti-apoptotic by regulating the NF-κB/STAT3/SOCS3 signaling pathway

Abstract

Septic myocardial injury, a severe sepsis complication linked to high morbidity and mortality, remains a major global clinical challenge. Interleukin-33 (IL-33), a damage-associated pro-inflammatory factor, has been implicated in regulating immune responses and inflammation, but its specific role in septic myocardial injury has not been fully elucidated. This study examined IL-33’s role in septic myocardial injury using Gene Expression Omnibus (GEO) database datasets, alongside in vitro and in vivo experiments. Our results indicated a significant upregulation of IL-33 in septic myocardial injury, as demonstrated in both clinical and experimental settings. Blocking IL-33 significantly enhanced cardiac function and alleviated cardiomyocyte damage. Mechanistic investigations revealed that neutralizing IL-33 mitigates inflammation, oxidative stress, and apoptosis in cardiomyocytes by regulating the nuclear factor kappa B (NF-κB)/signal transducer and activator of transcription 3 (STAT3)/suppressors of cytokine signaling 3 (SOCS3) signaling pathway. Peritoneal macrophages are recognized as a potential origin of IL-33, and targeting IL-33 derived from these cells further reduced cardiomyocyte injury. The study underscores IL-33’s crucial involvement in septic myocardial injury pathogenesis, indicating that IL-33 may serve as a promising therapeutic target.