Research ArticleSEPSIS

MEG3-4 is a miRNA decoy that regulates IL-1β abundance to initiate and then limit inflammation to prevent sepsis during lung infection

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Science Signaling  26 Jun 2018:
Vol. 11, Issue 536, eaao2387
DOI: 10.1126/scisignal.aao2387

Inflammatory decoy control

Inflammation resulting from bacterial infection can lead to sepsis and death if unresolved. The inflammatory response is dynamically regulated by long noncoding RNAs (lncRNAs). Li et al. examined tissue from mice intranasally infected with various bacterial strains and compared those with tissues from healthy controls. The lncRNA MEG3-4 and the mRNA encoding the proinflammatory cytokine IL-1β competitively bound to the microRNA miR-138 in the lungs. This facilitated bacterial infection–induced production of IL-1β, which activated pathways that reduced the abundance of MEG3-4 and increased that of miR-138, subsequently reducing IL-1β abundance and inflammatory signaling. Overexpressing MEG3-4 in the lungs exacerbated inflammation, prolonged infection, and enabled bacterial dissemination, which caused lung injury in mice, whereas intravenously delivering miR-138 mimics to infected mice enhanced their survival. These findings suggest how a feedback loop in the innate immune system may be manipulated to prevent lung injury and sepsis during pulmonary infection.


Long noncoding RNAs (lncRNAs) regulate gene expression. We investigated the role of lncRNAs in the inflammatory response to bacterial infection in the lungs. We identified the lncRNA MEG3 as a tissue-specific modulator of inflammatory responses during bacterial infection. Among the 10 transcript isoforms of MEG3, transcript 4 (referred to as MEG3-4) encodes the isoform with the lowest abundance in mouse lungs. Nonetheless, we found that MEG3-4 bound to the microRNA miR-138 in a competitive manner with mRNA encoding the proinflammatory cytokine interleukin-1β (IL-1β), thereby increasing IL-1β abundance and intensifying inflammatory responses to bacterial infection in alveolar macrophages and lung epithelial cells in culture and in lung tissue in mice. MEG3-4–mediated sponging of miR-138 in the cytoplasm increased the autocrine activity of IL-1β that subsequently induced a negative feedback mechanism mediated by nuclear factor κB that decreased MEG3-4 abundance and inflammatory cytokine production. This timely reduction in MEG3-4 abundance tempered proinflammatory responses in mice with pulmonary bacterial infection, preventing the progression to sepsis. Together, these findings reveal that MEG3-4 dynamically modulates pulmonary inflammatory responses through transcriptional regulation of immune response genes, extending the decoy and sponge mechanism associated with lncRNAs to antibacterial immunity, which affects both response and disease progression.

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