PMID- 30676324 OWN - NLM STAT- MEDLINE DCOM- 20200511 LR - 20220823 IS - 2379-3708 (Electronic) IS - 2379-3708 (Linking) VI - 4 IP - 4 DP - 2019 Feb 21 TI - Long noncoding RNA Malat1 regulates differential activation of macrophages and response to lung injury. LID - 124522 [pii] LID - 10.1172/jci.insight.124522 [doi] LID - e124522 AB - Macrophage activation, i.e., classical M1 and the alternative M2, plays a critical role in many pathophysiological processes, such as inflammation and tissue injury and repair. Although the regulation of macrophage activation has been under extensive investigation, there is little knowledge about the role of long noncoding RNAs (lncRNAs) in this event. In this study, we found that lncRNA Malat1 expression is distinctly regulated in differentially activated macrophages in that it is upregulated in LPS-treated and downregulated in IL-4-treated cells. Malat1 knockdown attenuates LPS-induced M1 macrophage activation. In contrast, Malat1 knockdown enhanced IL-4-activated M2 differentiation as well as a macrophage profibrotic phenotype. Mechanistically, Malat1 knockdown led to decreased expression of Clec16a, silencing of which phenocopied the regulatory effect of Malat1 on M1 activation. Interestingly, Malat1 knockdown promoted IL-4 induction of mitochondrial pyruvate carriers (MPCs) and their mediation of glucose-derived oxidative phosphorylation (OxPhos), which was crucial to the Malat1 regulation of M2 differentiation and profibrotic phenotype. Furthermore, mice with either global or conditional myeloid knockout of Malat1 demonstrated diminished LPS-induced systemic and pulmonary inflammation and injury. In contrast, these mice developed more severe bleomycin-induced lung fibrosis, accompanied by alveolar macrophages displaying augmented M2 and profibrotic phenotypes. In summary, we have identified what we believe is a previously unrecognized role of Malat1 in the regulation of macrophage polarization. Our data demonstrate that Malat1 is involved in pulmonary pathogeneses in association with aberrant macrophage activation. FAU - Cui, Huachun AU - Cui H AD - Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA. FAU - Banerjee, Sami AU - Banerjee S AD - Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA. FAU - Guo, Sijia AU - Guo S AD - Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA. AD - Department of Pulmonary, Allergy, and Critical Care Medicine, The Second Affiliated Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin, China. FAU - Xie, Na AU - Xie N AD - Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA. FAU - Ge, Jing AU - Ge J AD - Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA. AD - Department of Geriatrics and Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Jiang, Dingyuan AU - Jiang D AD - Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA. AD - Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, Beijing, China. FAU - Zornig, Martin AU - Zornig M AD - Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany. FAU - Thannickal, Victor J AU - Thannickal VJ AD - Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA. FAU - Liu, Gang AU - Liu G AD - Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA. LA - eng GR - I01 BX003056/BX/BLRD VA/United States GR - P01 HL114470/HL/NHLBI NIH HHS/United States GR - R01 HL126737/HL/NHLBI NIH HHS/United States GR - R35 HL135830/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190221 PL - United States TA - JCI Insight JT - JCI insight JID - 101676073 RN - 0 (CLEC16A protein, mouse) RN - 0 (Lectins, C-Type) RN - 0 (Lipopolysaccharides) RN - 0 (Malat1 long non-coding RNA, mouse) RN - 0 (Monosaccharide Transport Proteins) RN - 0 (RNA, Long Noncoding) RN - 11056-06-7 (Bleomycin) SB - IM MH - Acute Lung Injury/diagnosis/genetics/*immunology MH - Animals MH - Bleomycin/toxicity MH - Bronchoalveolar Lavage Fluid MH - Cell Differentiation/genetics/immunology MH - Disease Models, Animal MH - Down-Regulation/immunology MH - Fibrosis MH - Gene Knockdown Techniques MH - Humans MH - Lectins, C-Type/*genetics/immunology MH - Lipopolysaccharides/administration & dosage/immunology MH - Lung/cytology/immunology/*pathology MH - Macrophage Activation/*genetics/immunology MH - Macrophages, Alveolar/*immunology/metabolism MH - Male MH - Mice MH - Mice, Knockout MH - Monosaccharide Transport Proteins/*genetics/immunology MH - RNA, Long Noncoding/genetics/*metabolism MH - Up-Regulation/genetics/immunology PMC - PMC6478413 OTO - NOTNLM OT - Cellular immune response OT - Fibrosis OT - Immunology OT - Macrophages OT - Pulmonology COIS- Conflict of interest: The authors declare that no conflict of interest exists. EDAT- 2019/01/25 06:00 MHDA- 2020/05/12 06:00 PMCR- 2019/02/21 CRDT- 2019/01/25 06:00 PHST- 2018/09/26 00:00 [received] PHST- 2019/01/17 00:00 [accepted] PHST- 2019/01/25 06:00 [pubmed] PHST- 2020/05/12 06:00 [medline] PHST- 2019/01/25 06:00 [entrez] PHST- 2019/02/21 00:00 [pmc-release] AID - 124522 [pii] AID - 10.1172/jci.insight.124522 [doi] PST - epublish SO - JCI Insight. 2019 Feb 21;4(4):e124522. doi: 10.1172/jci.insight.124522. eCollection 2019 Feb 21.