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MCC950 improves lipopolysaccharide‑induced systemic inflammation in mice by relieving pyroptosis in blood neutrophils
Runfeng Miao1,2, Jian Huang1
1Department of Emergency Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
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.
Insights
MCC950, an NLRP3 inhibitor, effectively treats sepsis by reducing inflammation and organ damage in mice. It targets neutrophil pyroptosis, decreasing oxidative stress and increasing survival rates.
Area of Science:
- Immunology
- Pharmacology
- Pathology
Background:
- Sepsis is a life-threatening condition characterized by systemic inflammation and organ dysfunction.
- NLR family pyrin domain containing 3 (NLRP3) inflammasome activation contributes to sepsis pathogenesis.
- MCC950 is a potent NLRP3 inhibitor with potential therapeutic benefits.
Purpose of the Study:
- To investigate the efficacy of MCC950 in a lipopolysaccharide (LPS)-induced mouse model of sepsis.
- To elucidate the underlying mechanisms of MCC950's protective effects, focusing on neutrophil pyroptosis.
Main Methods:
- C57BL/6 mice were subjected to LPS injection to induce sepsis, with or without MCC950 treatment.
- Histopathological analysis assessed organ damage.
- Inflammatory cytokine levels, reactive oxygen species (ROS), neutrophil apoptosis, and pyroptosis markers (GSDMD, NLRP3, caspase-1) were measured.
- Survival rates were analyzed.
Main Results:
- MCC950 treatment significantly alleviated LPS-induced organ damage and dysfunction.
- MCC950 reduced serum inflammatory cytokine levels.
- MCC950 inhibited LPS-induced oxidative stress and neutrophil apoptosis.
- MCC950 suppressed neutrophil pyroptosis by downregulating NLRP3, caspase-1, and GSDMD.
- MCC950 treatment improved survival rates in septic mice.
Conclusions:
- MCC950 demonstrates significant therapeutic potential for sepsis.
- MCC950 exerts its protective effects by inhibiting NLRP3-mediated neutrophil pyroptosis, reducing inflammation, and mitigating organ injury.
