Abstract
We recently reported the differential circRNA expression patterns of the pulmonary macrophages in sepsis-induced acute respiratory distress syndrome (ARDS) mice model by microarray analysis. However, their function and hidden molecular mechanism in regulation of macrophage activation and inflammation remain poorly understood. In this study, we found that circN4bp1was overexpressed in PBMC and monocytes, and its expression levels were correlated with a poor prognosis in sepsis induced ARDS patients induced by sepsis. Knockdown of circN4bp1 inhibited the lung injury and improved the long-time survival through blunting the M1 macrophage activation in cecal ligation and puncture- (CLP-) induced ARDS mice. Moreover, bioinformatics analysis predicated a circN4bp1/miR-138-5p ceRNA network, which was confirmed by luciferase reporter assay and RNA binding protein immunoprecipitation (RIP). CircN4bp1 affected macrophage differentiation by binding to miR-138-5p, thus regulating the expression of EZH2 in vivo and ex vivo. Lastly, the m6A level of circN4bp1was found to be elevated in ARDS mice; inhibition of m6A methyltransferase METTL3 blocked this response in vitro. Therefore, circN4bp1 can function as a miR-138-5p sponge for the modulation of macrophage polarization through regulation the expression of EZH2 and may serve as a potential target and/or prognostic marker for ARDS patients following sepsis.
Highlights
Sepsis is defined as progressive, inflammatory responses to overwhelming infections, and multiorgan dysfunction is the major cause of death
Increasing evidence has shown that macrophages are key players in the pathogenesis of acute respiratory distress syndrome (ARDS) induced by sepsis [3, 4], which can switch from an initial proinflammatory M1 phenotype during the phase of onset of lung injury to an anti-inflammatory M2 phenotype with initiation of lung repair stage [4]
We have recently reported the global changes in the circRNA expression patterns and circRNAmiRNA-mRNA networks of the pulmonary macrophage activation in a typical cecal ligation and puncture- (CLP-) induced ARDS mice model by microarray analysis, suggesting that circRNAs might make a vital contribution to the macrophage differentiation and the development of ARDS [11]
Summary
Sepsis is defined as progressive, inflammatory responses to overwhelming infections, and multiorgan dysfunction is the major cause of death. Several studies have highlighted the regulatory mechanisms by which circRNAs participate in gene regulation, functioning as miRNA “sponge” to sequester and competitively suppress miRNA activity [5], regulating transcription of genes and translating protein genes [5]. Their interactions with diseaseassociated miRNAs indicate that circRNAs are crucial in a variety of diseases and might serve as novel diagnostic biomarkers and therapeutic targets [6, 7]. The detailed role and molecular mechanism of circRNAs in macrophage polarization and sepsis-induced ARDS remain to be documented. The contributions of m6A modification for circRNAs in ARDS have not been elucidated
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