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Long Non-Coding RNA Malat1 Regulates Macrophage Polarization and Lung Injury and Fibrosis
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A6359 - Long Non-Coding RNA Malat1 Regulates Macrophage Polarization and Lung Injury and Fibrosis
Author Block: H. Cui, N. Xie, S. Banerjee, S. Guo, R. Liu, V. J. Thannickal, G. Liu; Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.
Rationale: Macrophage activations, i.e. the classical and alternative ones, play critical roles in many physio-pathological processes, such as inflammation, tissue injury and repair, and tumor progression. Macrophage activations are subject to regulations at multiple levels. However, there is little knowledge regarding the role of long non-coding RNAs (lncRNAs) in this process. It is unclear if or how lncRNA regulated macrophage activation participates in the pathogenesis of pulmonary disorders. Methods: Levels of lncRNA Malat1 were determined in differentially activated mouse macrophages. Macrophage activations were compared in cells with or without Malat1. Mice with conditional knockout of Malat1 in macrophages were used to evaluate the effect of macrophage Malat1 on endotoxin induced acute lung injury and bleomycin induced lung fibrosis. Results: We found that Malat1 was upregulated in LPS treated, whereas downregulated in IL-4 activated macrophages. We found that Malat1 knockdown in macrophages significantly attenuated LPS induced inflammatory response. In contrast, Malat1 knockdown enhanced IL-4 mediated alternative activation. Mechanistically, we found that Malat1 knockdown promoted mitochondrial oxidative phosphorylation in alternatively activated macrophages. Furthermore, we found that mice with conditional knockout of macrophage Malat1 demonstrated diminished LPS induced lung injury. However, these mice developed more severe lung fibrosis after intratracheal delivery of bleomycin. Conclusions: Our data indicate that Malat1 plays a critical role in the regulation of macrophage polarization, and thereby it contributes to the pathogenesis of lung injury and repair. Our study also suggests Malat1 as a previously unrecognized target for developing novel therapeutics to treat these pulmonary disorders.
Author Block: H. Cui, N. Xie, S. Banerjee, S. Guo, R. Liu, V. J. Thannickal, G. Liu; Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.
Rationale: Macrophage activations, i.e. the classical and alternative ones, play critical roles in many physio-pathological processes, such as inflammation, tissue injury and repair, and tumor progression. Macrophage activations are subject to regulations at multiple levels. However, there is little knowledge regarding the role of long non-coding RNAs (lncRNAs) in this process. It is unclear if or how lncRNA regulated macrophage activation participates in the pathogenesis of pulmonary disorders. Methods: Levels of lncRNA Malat1 were determined in differentially activated mouse macrophages. Macrophage activations were compared in cells with or without Malat1. Mice with conditional knockout of Malat1 in macrophages were used to evaluate the effect of macrophage Malat1 on endotoxin induced acute lung injury and bleomycin induced lung fibrosis. Results: We found that Malat1 was upregulated in LPS treated, whereas downregulated in IL-4 activated macrophages. We found that Malat1 knockdown in macrophages significantly attenuated LPS induced inflammatory response. In contrast, Malat1 knockdown enhanced IL-4 mediated alternative activation. Mechanistically, we found that Malat1 knockdown promoted mitochondrial oxidative phosphorylation in alternatively activated macrophages. Furthermore, we found that mice with conditional knockout of macrophage Malat1 demonstrated diminished LPS induced lung injury. However, these mice developed more severe lung fibrosis after intratracheal delivery of bleomycin. Conclusions: Our data indicate that Malat1 plays a critical role in the regulation of macrophage polarization, and thereby it contributes to the pathogenesis of lung injury and repair. Our study also suggests Malat1 as a previously unrecognized target for developing novel therapeutics to treat these pulmonary disorders.
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