First published January 24, 2019 - More info
Macrophage activation, i.e., the 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 investigations, there is little knowledge about the role of long non-coding RNAs (lncRNAs) in the event. In this study, we found that lncRNA Malat1 expression is distinctly regulated in differentially activated macrophages in that it is upregulated in LPS-, whereas 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 macrophage pro-fibrotic phenotype. Mechanistically, Malat1 knockdown led to decreased expression of Clec16a, of which silencing 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 pro-fibrotic phenotype. Furthermore, mice with either global or conditional myeloid knockout of Malat1 demonstrated diminished LPS induced systemic and pulmonary inflammation and injury. Conversely, these mice developed more severe bleomycin induced lung fibrosis, accompanied by alveolar macrophages displaying augmented M2 and pro-fibrotic phenotype. In summary, we have identified a previously unrecognized role of Malat1 in regulation of macrophage polarization. Our data demonstrate that Malat1 is involved in pulmonary pathogeneses in association with aberrant macrophage activation.