Inhibition of miR-155 potentially protects against lipopolysaccharide-induced acute lung injury through the IRF2BP2-NFAT1 pathway
Authors:
- 1 December 2020
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 319 (6) , C1070-C1081
Abstract
Sepsis-induced lung injury is a lethal complication with no effective treatment options, affecting millions of people worldwide. Oroxylin A (OroA) is a natural flavonoid with potent anticancer effects, but its modulating effect on inflammation through microRNAs (miRs) is not apparent. In this report, we investigated the target genes of the miR pathway mediated by OroA and assessed the potential for novel treatments of septic lung injury. An miR array screening and quantitative polymerase chain reaction identified that miR-155-5p could be a candidate regulated by OroA. Bioinformatics analysis indicated that interferon regulatory factor-2-binding protein-2 (IRF2BP2) might be a target of miR-155-5p, and this hypothesis was verified through reporter assays. In addition, an immunoprecipitation assay demonstrated that OroA increased the binding activity of IRF2BP2 to the nuclear factor of activated T-cells 1 (NFAT1), causing inducible nitric oxide synthase to cause an inflammatory reaction. Finally, the direct injection of short hairpin RNA (shRNA)-miR-155-5p into the bone marrow of mice ameliorated LPS-induced acute lung injury and inflammation in mice. Our results provide new mechanistic insights into the role of the OroA-induced miR-155-5p-IRF2BP2-NFAT1 axis in sepsis, demonstrating that direct bone marrow injection of lentivirus containing shRNA-155-5p could prove to be a potential future clinical application in alleviating sepsis-induced acute lung injury.Keywords
Funding Information
- Ministry of Science and Technology, Taiwan (103-2314-B-038-016-MY3)
- Ministry of Science and Technology, Taiwan (104-2314-B-038-047-MY2)
- Ministry of Science and Technology, Taiwan (104-2314-B-303-014-MY3)
- Ministry of Science and Technology, Taiwan (107-2314-B-038-092)
- Ministry of Science and Technology, Taiwan (106-2314-B-038-064-MY3)
- Taipei Medical University (104TMU-TMUH-10)
- Taipei Medical University (106TMU-TMUH-13)
This publication has 62 references indexed in Scilit:
- Oroxylin-A Rescues LPS-Induced Acute Lung Injury via Regulation of NF-κB Signaling Pathway in RodentsPLOS ONE, 2012
- Interferon Regulatory Factor 2 Binding Protein 2 Is a New NFAT1 Partner and Represses Its Transcriptional ActivityMolecular and Cellular Biology, 2011
- Critical Role for Oxidative Stress, Platelets, and Coagulation in Capillary Blood Flow Impairment in SepsisMicrocirculation, 2011
- Molecular mechanism underlying the suppression of lipid oxidation during endotoxemiaMolecular Immunology, 2009
- Inositol phosphatase SHIP1 is a primary target of miR-155Proceedings of the National Academy of Sciences, 2009
- Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signalsProceedings of the National Academy of Sciences, 2009
- Cooperative NCoR/SMRT interactions establish a corepressor-based strategy for integration of inflammatory and anti-inflammatory signaling pathwaysGenes & Development, 2009
- NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responsesProceedings of the National Academy of Sciences, 2006
- The NRIF3 Family of Transcriptional Coregulators Induces Rapid and Profound Apoptosis in Breast Cancer CellsMolecular and Cellular Biology, 2004
- Sustained Lipopolysaccharide-Induced Lung Inflammation in Mice Is Attenuated by Functional Deficiency of the Fas/Fas Ligand SystemClinical and Vaccine Immunology, 2004