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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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机构： [1]Key Laboratory of Biotechnology for Medicinal Plants of Jiangsu Province and School of Life Sciences, Jiangsu Normal University, Xuzhou, Jiangsu 221116, P. R. China. [2]Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND 58203–9037, USA. [3]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, P. R. China. [4]Altru Hospital, Grand Forks, ND 58203, USA. [5]Department of Pediatrics and Department of Biomedical and Health Informatics, Children’s Mercy Hospital, University of Missouri–Kansas City School of Medicine, Kansas City, MO 64108, USA. [6]State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, Sichuan 400042, P. R. China.

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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. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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出版当年[2018]版：

大类 | 1 区

生物

小类 | 2 区生化与分子生物学 2 区细胞生物学

最新[2023]版：

大类 | 1 区

生物学

小类 | 2 区生化与分子生物学 2 区细胞生物学

第一作者：

第一作者机构： [1]Key Laboratory of Biotechnology for Medicinal Plants of Jiangsu Province and School of Life Sciences, Jiangsu Normal University, Xuzhou, Jiangsu 221116, P. R. China. [2]Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND 58203–9037, USA.

通讯作者：

通讯机构： [2]Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND 58203–9037, USA. [3]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, P. R. China.

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