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.

长非编码RNA（lncRNA）调节基因表达。我们调查了lncRNA在肺部细菌感染的炎症反应中的作用。我们确定lncRNA MEG3是细菌感染过程中炎症反应的组织特异性调节剂。在MEG3的10种转录本同工型中，转录本4（称为MEG3-4）编码小鼠肺中丰度最低的同工型。尽管如此，我们发现MEG3-4与编码促炎性细胞因子白介素-1β（IL-1β）的mRNA竞争性结合至microRNA miR-138，从而增加了IL-1β的丰度并增强了对肺泡巨噬细胞中细菌感染的炎症反应和小鼠肺组织中的肺上皮细胞。MEG3-4介导的miR-138在细胞质中的海绵增强了IL-1β的自分泌活性，随后诱导了由核因子κB介导的负反馈机制，从而降低了MEG3-4的丰度和炎性细胞因子的产生。肺细菌感染小鼠中MEG3-4丰度的这种适时降低会缓解促炎反应，从而阻止败血症的发展。总之，这些发现表明，MEG3-4通过免疫应答基因的转录调节来动态调节肺部炎症反应，从而将与lncRNA相关的诱饵和海绵机制扩展至抗菌免疫，从而影响应答和疾病进展。