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

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 4

Myeloid ablation of Malat1 (Malat1 mye–/–) attenuates LPS-induced ALI.

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Myeloid ablation of Malat1 (Malat1 mye–/–) attenuates LPS-induced ALI. (...
(A) Alveolar macrophages were harvested from BALFs of Malat1fl/fl and Malat1 mye–/– mice. Levels of Malat1 in the cells were determined by real-time PCR. n = 6 each for Malat1fl/fl and Malat1 mye–/– mice; mean ± SE. (B and C) Malat1fl/fl and Malat1 mye–/– mice were i.t. instilled with 50 μl saline or 5 mg/kg LPS in 50 μl saline. Forty-eight hours after administration, mice were sacrificed and lung homogenates prepared. Levels of the indicated proinflammatory cytokines were determined by ELISA. n = 3, 6, 5, 6 mice for each group; mean ± SE. (D–F) Experiments were performed as in B and C. BALF levels of the indicated proinflammatory cytokines were determined by ELISA. n = 4, 6, 3, 6 mice for each group; mean ± SE. (G) Experiments were performed as in B and C. Levels of lung MPO were determined by ELISA. n = 3, 6, 5, 5 mice for each group; mean ± SE. (H) Experiments were performed as in B and C. H&E staining was performed. Original magnification, ×10. Scale bars: 200 μm. (I) Experiments were performed as in B and C. Twenty-four hours after administration, alveolar macrophages were harvested and mRNA levels of the indicated genes determined by real-time PCR. ● Malat1fl/fl saline, ■ Malat1fl/fl LPS, ▲ Malat1 mye–/– saline, ▼ Malat1 mye–/– LPS; n = 6, 4, 6, 4 mice for each group; mean ± SE. (J) Experiments were performed as in B and C. Twenty-four hours after administration, alveolar macrophages were harvested and mRNA levels of Clec16a determined. n = 4, 4 mice for each group; mean ± SE. *P < 0.05; **P < 0.01; ***P < 0.001 by 1-way ANOVA with Bonferroni’s post hoc test (B–I) or 2-tailed Student’s t test (J).