MCC950 improves lipopolysaccharide‑induced systemic inflammation in mice by relieving pyroptosis in blood neutrophils.

Abstract

Sepsis is an infection-induced systemic inflammatory response syndrome accompanied by multiple organ injury and failure. MCC950, an inhibitor of NLR family pyrin domain containing 3 (NLRP3), can alleviate the inflammatory response and relieve inflammation-induced injury. The aim of the present study was to explore the efficacy of MCC950 in lipopolysaccharide (LPS)-induced inflammation and elucidate the underlying mechanisms. Based on a prior study, C57BL/6 mice were divided into three groups: Control, LPS, and LPS + MCC950. The mice were administered 10 mg/kg LPS to induce sepsis and 10 mg/kg MCC950 to treat sepsis 6 h before and after LPS injection. Histopathological imaging revealed organ morphology and damage during inflammation, and MCC950 alleviated organ damage and dysfunction. MCC950 prevented LPS-induced inflammatory responses by reducing inflammatory cytokine levels in the blood. To explore the mechanism by which MCC950 functions, blood neutrophils were isolated and a series of tests were performed. As revealed by measuring reactive oxygen species levels and Annexin V/PI staining of neutrophils, MCC950 reduced oxidative stress and programmed death induced by LPS. Western blotting was used to assess the protein levels of pyroptosis-related markers, including GSDMD, NLRP3, and caspase-1, in neutrophils to further explore the form of death. MCC950 reduced LPS-induced pyroptosis in neutrophils. The results of the survival analysis revealed that MCC950 increased the survival rates of mice within 72 h of LPS injection. MCC950 may be an effective treatment for sepsis that targets neutrophil pyroptosis.