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Published on: May 21, 2018
CircMLH3 induces mononuclear macrophage pyroptosis in sepsis by sponging miR-590-3p to regulate TAK1 expression
Qin Sun1, Zihan Hu1, Wei Huang1
1Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
Abstract:
Sepsis is a fatal syndrome characterized by uncontrolled systemic inflammatory responses. Circular RNAs (circRNAs) are involved in the modulation of various pathophysiological processes, but their potential role in sepsis has largely been unexplored. In this study, we observed differential expression of circMLH3 between healthy volunteers and septic patients, and revealed the value of circMLH3 for sepsis diagnosis and prognostic prediction. Interestingly, we discovered a correlation between the expression level of circMLH3 and the degree of pyroptosis, a critical mechanism contributing to uncontrolled inflammation in sepsis patients. Knocking down circMLH3 alleviated macrophage pyroptosis whereas overexpressing circMLH3 aggravated pyroptosis. circMLH3 regulated macrophage pyroptosis by sponging miR-590-3p and subsequently modulating TAK1 expression. Furthermore, we found that the miR-590-3p/TAK1 axis inhibited the activation of pro-caspase-1 and the NLRP3 inflammasome. miR-590-3p overexpression had a protective effect by reducing macrophage pyroptosis, thereby alleviating sepsis-induced lung injury and systemic inflammatory responses. In conclusion, our study elucidated the circMLH3/miR-590-3p/TAK1 signaling pathway and identified its role in regulating mononuclear macrophage pyroptosis, thus providing potential novel targets and strategies for sepsis diagnosis and therapy.
Insights
Circular RNAs (circRNAs) like circMLH3 are implicated in sepsis. This study reveals circMLH3 regulates macrophage pyroptosis via the miR-590-3p/TAK1 axis, offering potential diagnostic and therapeutic targets for sepsis.
Area of Science:
- Molecular Biology
- Immunology
- Genetics
Background:
- Sepsis is a life-threatening condition driven by uncontrolled inflammation.
- Circular RNAs (circRNAs) are increasingly recognized for their roles in disease, but their function in sepsis remains unclear.
- Pyroptosis, a form of programmed cell death, is a key inflammatory mechanism in sepsis.
Purpose of the Study:
- To investigate the role of circMLH3 in sepsis.
- To explore the diagnostic and prognostic value of circMLH3 in sepsis patients.
- To elucidate the molecular mechanisms underlying circMLH3-mediated regulation of pyroptosis in sepsis.
Main Methods:
- Differential expression analysis of circMLH3 in healthy volunteers and septic patients.
- In vitro experiments involving circMLH3 knockdown and overexpression in macrophages.
- RNA sequencing and molecular assays to investigate the circMLH3/miR-590-3p/TAK1 pathway.
- Assessment of pyroptosis, inflammasome activation, and inflammatory responses in vivo and in vitro.
Main Results:
- circMLH3 expression is differentially expressed in sepsis and correlates with disease severity.
- circMLH3 promotes macrophage pyroptosis by sponging miR-590-3p, leading to increased TAK1 expression.
- The miR-590-3p/TAK1 axis modulates pro-caspase-1 and NLRP3 inflammasome activation.
- Overexpression of miR-590-3p alleviates sepsis-induced lung injury and systemic inflammation.
Conclusions:
- The circMLH3/miR-590-3p/TAK1 signaling pathway plays a critical role in regulating macrophage pyroptosis during sepsis.
- circMLH3 serves as a potential biomarker for sepsis diagnosis and prognosis.
- Targeting this pathway offers novel therapeutic strategies for sepsis management.
