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Background <p>Sepsis is a life-threatening condition associated with high morbidity and mortality, frequently resulting in acute lung injury (ALI) as one of its most severe complications. The pathogenesis of sepsis-induced ALI is significantly influenced by excessive inflammation, particularly that mediated by macrophages, plays a critical role in the pathogenesis of sepsis-induced ALI. This study sought to explore the protective effects and underlying mechanisms of adipose-derived stem cell exosomes (ADSCs-exo) on macrophage-mediated inflammation and pyroptosis.</p> Methods <p>ADSCs-exo were isolated and characterized using nanoparticle tracking analysis (NTA), Western blotting, and transmission electron microscopy. A macrophage pyroptosis model was established through lipopolysaccharide (LPS) stimulation. The effects of ADSCs-exo on the secretion of inflammatory cytokine and pyroptosis-related markers (NLRP3, Caspase1, GSDMD) was evaluated. Mechanistic studies included dual-luciferase reporter assays and NLRP3 inhibition experiments. In vivo, a cecal ligation and puncture (CLP) sepsis model was utilized to evaluate the impact of ADSCs-exo on pulmonary inflammation, histopathological damage, survival rates, macrophage polarization (M1/M2), and components of the pyroptosis pathway (NLRP3, Caspase1).</p> Results <p>Isolated ADSCs-exo displayed characteristic features of exosomes. The administration of ADSCs-exo mitigated LPS-induced hyperinflammation in macrophages, which was associated with a decreased expression of pyroptosis executors, namely Caspase1, GSDMD and NLRP3. Mechanistically, ADSCs-exo facilitated the delivery of miR-24-3p, which specifically targeted NLRP3 to inhibit pyroptosis. In mice subjected to CLP-challenge, the administration of ADSCs-exo improved lung pathology, enhanced survival rates, and reduced markers of pyroptosis in pulmonary tissues.</p> Conclusions <p>Our findings indicate that ADSCs-exo attenuates ALI by modulating macrophage pyroptosis through the miR-24-3p/NLRP3/Caspase1/GSDMD axis, thereby presenting a promising therapeutic approach for sepsis-associated ALI.</p>

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MiR-24-3p delivered by adipose derived stem cells exosomes alleviate macrophage pyroptosis via NLRP3/Caspase1/GSDMD in sepsis ALI

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月27日

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  • Kuo Shen,
  • Peng Wang,
  • Hao Zhang,
  • Xianqi Wang,
  • Heliang Fu,
  • Jin Li,
  • Jijun Chen,
  • Peng Zhao,
  • Wenjie Cheng,
  • Yuhang Wang,
  • Ruizhi Wang,
  • Rui Zheng,
  • Dahai Hu,
  • Junjie Li

摘要

Background

Sepsis is a life-threatening condition associated with high morbidity and mortality, frequently resulting in acute lung injury (ALI) as one of its most severe complications. The pathogenesis of sepsis-induced ALI is significantly influenced by excessive inflammation, particularly that mediated by macrophages, plays a critical role in the pathogenesis of sepsis-induced ALI. This study sought to explore the protective effects and underlying mechanisms of adipose-derived stem cell exosomes (ADSCs-exo) on macrophage-mediated inflammation and pyroptosis.

Methods

ADSCs-exo were isolated and characterized using nanoparticle tracking analysis (NTA), Western blotting, and transmission electron microscopy. A macrophage pyroptosis model was established through lipopolysaccharide (LPS) stimulation. The effects of ADSCs-exo on the secretion of inflammatory cytokine and pyroptosis-related markers (NLRP3, Caspase1, GSDMD) was evaluated. Mechanistic studies included dual-luciferase reporter assays and NLRP3 inhibition experiments. In vivo, a cecal ligation and puncture (CLP) sepsis model was utilized to evaluate the impact of ADSCs-exo on pulmonary inflammation, histopathological damage, survival rates, macrophage polarization (M1/M2), and components of the pyroptosis pathway (NLRP3, Caspase1).

Results

Isolated ADSCs-exo displayed characteristic features of exosomes. The administration of ADSCs-exo mitigated LPS-induced hyperinflammation in macrophages, which was associated with a decreased expression of pyroptosis executors, namely Caspase1, GSDMD and NLRP3. Mechanistically, ADSCs-exo facilitated the delivery of miR-24-3p, which specifically targeted NLRP3 to inhibit pyroptosis. In mice subjected to CLP-challenge, the administration of ADSCs-exo improved lung pathology, enhanced survival rates, and reduced markers of pyroptosis in pulmonary tissues.

Conclusions

Our findings indicate that ADSCs-exo attenuates ALI by modulating macrophage pyroptosis through the miR-24-3p/NLRP3/Caspase1/GSDMD axis, thereby presenting a promising therapeutic approach for sepsis-associated ALI.