M1 Macrophage-Derived Exosomes Promote Intestinal Barrier Dysfunction and Pyroptosis in Sepsis by Modulating NLRP3...

Area of Science:

• Immunology
• Gastroenterology
• Cell Biology

Background:

• Intestinal barrier dysfunction is critical in sepsis progression.
• M1 macrophage-derived exosomes (M1-Exos) contribute to gut inflammation.
• The specific roles of M1-Exos in sepsis-induced gut barrier injury require elucidation.

Purpose of the Study:

• To investigate the role of M1-Exos in sepsis-induced gut barrier injury.
• To identify the underlying molecular mechanisms involving NEAT1 and NLRP3 inflammasome.
• To explore potential therapeutic targets for septic gut barrier injury.

Main Methods:

• Exosomes from M1 macrophages were injected into mice to assess impacts on intestinal barrier, NLRP3 inflammasome, and intestinal epithelial cells (IECs) pyroptosis.
• LncRNA NEAT1 expression was analyzed in macrophages and their exosomes.
• Gene knockout mice and in vitro experiments were used to determine NEAT1 function and its interaction with NLRP3.

Main Results:

• M1-Exos injection in mice led to barrier impairment, NLRP3 inflammasome activation, and IECs pyroptosis.
• NEAT1 was highly expressed in M1-Exos from both mice and humans.
• NEAT1 deficiency protected against sepsis-induced gut injury, and exosomal NEAT1 directly activated the NLRP3 inflammasome by binding to NLRP3.

Conclusions:

• Gut-resident M1 macrophages release exosomal NEAT1, which exacerbates sepsis-induced gut barrier injury.
• Exosomal NEAT1 promotes IECs pyroptosis by activating the NLRP3 inflammasome.
• Exosomal NEAT1 represents a promising therapeutic target for septic gut barrier injury.