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Long noncoding RNA Malat1 regulates differential activation of macrophages and response to lung injury
Huachun Cui, … , Victor J. Thannickal, Gang Liu
Huachun Cui, … , Victor J. Thannickal, Gang Liu
Published January 24, 2019
Citation Information: JCI Insight. 2019;4(4):e124522. https://doi.org/10.1172/jci.insight.124522.
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Research Article Immunology Pulmonology

Long noncoding RNA Malat1 regulates differential activation of macrophages and response to lung injury

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Abstract

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.

Authors

Huachun Cui, Sami Banerjee, Sijia Guo, Na Xie, Jing Ge, Dingyuan Jiang, Martin Zörnig, Victor J. Thannickal, Gang Liu

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Figure 1

lncRNA Malat1 expression undergoes distinct alteration in differentially activated macrophages.

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lncRNA Malat1 expression undergoes distinct alteration in differentially...
(A) Mouse BMDMs were treated with 100 ng/ml LPS for the indicated duration of time. Total RNAs were isolated and levels of Malat1 determined by real-time PCR. n = 4; mean ± SD; *P < 0.05, **P < 0.01 compared with time “0”. (B) Human PBMC-derived macrophages were treated with 100 ng/ml LPS for the indicated duration of time. Levels of Malat1 were determined. n = 4; mean ± SD; **P < 0.01 compared with time “0”. (C) Human THP-1–derived macrophages were treated with 100 ng/ml LPS for the indicated duration of time. Levels of Malat1 were determined. n = 3; mean ± SD; *P < 0.05 compared with time “0”. (D) BMDMs were treated with or without 100 ng/ml LPS for 1 hour. ChIP assay was performed. Levels of p65 binding to the Malat1 promoter were determined by real-time PCR. n = 3; mean ± SD; ***P < 0.001 compared with “–LPS”. (E) BMDMs were treated with 5 ng/ml mouse IL-4 for the indicated duration of time. Levels of Malat1 were determined. n = 4; mean ± SD; **P < 0.01 compared with time “0”. (F and G) BMDMs were treated with or without 100 ng/ml LPS for 6 hours or 5 ng/ml IL-4 for 24 hours. Cell fractionation was performed, and RNAs in the cytoplasmic and nuclear fractions were isolated. Levels of tubulin α1 and Sno-142 (F), and Malat1 (G) in each fraction were determined by real-time PCR. n = 3; mean ± SD; **P < 0.01, ***P < 0.001. Two-tailed Student’s t test was used (A–G) to analyze statistical significance. Representative of 2 to 3 independent experiments.

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