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Published on: May 21, 2018
M1 Macrophage-Derived Exosomes Promote Intestinal Barrier Dysfunction and Pyroptosis in Sepsis by Modulating NLRP3
Tao Yang1, Zhifen Wang2, Haiyan Wu1
1Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin Institute of Anesthesiology, Tianjin, China.
Background:
Intestinal barrier injury is pivotal in sepsis deterioration. M1 macrophage-derived exosomes (M1-Exos) promote gut inflammation. We aimed to reveal the roles of M1-Exos in sepsis-induced gut barrier injury and underlying mechanisms.
Methods:
Exosomes from ileum lamina propria macrophages were intraperitoneally injected into healthy mice to evaluate the impacts on intestinal barrier, NLRP3 inflammasome, and intestinal epithelial cells (IECs) pyroptosis. Long noncoding RNA NEAT1 was detected in mouse lamina propria macrophages and human monocyte-derived macrophages, as well as these macrophage-derived exosomes. The functions of NEAT1 were further investigated using gene knockout mice and in vitro experiments. The potential interaction between NEAT1 and NLRP3 was assessed via RNA pull-down and RNA-binding protein immunoprecipitation.
Results:
Ileum lamina propria macrophages from cecal ligation and puncture mice expressed M1 biomarkers. Mice M1-Exos (M-M1-Exos) injection caused barrier impairment, NLRP3 inflammasome activation and IECs pyroptosis. NEAT1 is highly expressed in both human M1-Exos and M-M1-Exos. In NEAT1 knockout mice, cecal ligation and puncture only caused slight barrier impairment and NLRP3 inflammasome activation without IECs pyroptosis, which were again aggravated by supplementary M-M1-Exos injection. In vitro , treating human IEC with human M1-Exos-caused barrier damage and NLRP3 inflammasome-mediated pyroptosis. These impairments were inapparent when human IEC was exposed to exosomes that lacked NEAT1 . Moreover, exosomal NEAT1 combined with NLRP3 to activate the NLRP3 inflammasome.
Conclusion:
These findings revealed that gut-resident M1 macrophages secreted exosomal NEAT1 to promote IECs pyroptosis via activating NLRP3 inflammasome, which provided a therapeutic target for septic gut barrier injury.
Insights
M1 macrophage-derived exosomes promote sepsis-induced gut barrier injury by delivering NEAT1, which activates the NLRP3 inflammasome and causes intestinal epithelial cell pyroptosis. This highlights exosomal NEAT1 as a therapeutic target for septic gut damage.
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.
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