ROS feedback regulates the microRNA-19-targeted inhibition of the p47phox-mediated LPS-induced inflammatory response.

Abstract

In acute lung injury/acute respiratory distress syndrome (ALI/ARDS), pathogenesis is associated with the regulation of macrophage-generated oxidative stress, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-derived reactive oxygen species(ROS) are key to regulating oxidative stress. In the present study, we found that miR-19 inhibited the expression of p47phox in macrophages, resulting in the alleviation of the lipopolysaccharides(LPS)-induced inflammatory response. In a mouse LPS-induced model of lung injury, miR-19-deficient murine lung tissue was more susceptible to inflammatory responses and exhibited a higher infiltration rate, a higher number of inflammatory cells in the lungs, a higher level of inflammatory cytokines in the Bronchoalveolar lavage fluid (BALF), and more severe pathological damage in lung tissues. Moreover, following stimulation with LPS, p47phox was expressed at lower levels in miR-19-deficient murine pulmonary inflammatory cells than in those in wild-type rats. In LPS-treated Raw264.7 macrophages, miR-19 mimics blocking the down-regulation of LPS-induced p47phox expression, the accumulation of ROS, and the release of inflammatory cytokines. When siRNA was used to interfere with p47phox expression following stimulation with LPS, a lower level of ROS-mediated inflammatory cytokines were released. We found that the accumulation of ROS inhibited the LPS-induced release of inflammatory cytokines, the upregulation of miR-19 and the down-regulation of LPS-induced p47phox expression. Finally, we constructed a p47phox 3'UTR luciferase reporter plasmid to provide direct confirmation that miR-19 targets p47phox expression. The results of this study indicate the presence of a mechanism by which miR-19 regulates oxidative stress in macrophages. These data also provide potential targets for studies aimed at developing therapies for ARDS.

• Authors: Tian Wang, Ya-Ping Liu, Ting Wang, Bang-Qiang Xu, Bo Xu
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 489 Issue 4 Pg. 361-368 (08 05 2017) ISSN: 1090-2104 [Electronic] United States
• PMID: 28479245 (Publication Type: Journal Article)
• Copyright: Copyright © 2017. Published by Elsevier Inc.

Chemical References

• Lipopolysaccharides
• MIRN19 microRNA, mouse
• MicroRNAs
• RNA, Small Interfering
• Reactive Oxygen Species
• NADPH Oxidases
• neutrophil cytosolic factor 1

Topics

• Animals
• Cells, Cultured
• Inflammation (metabolism)
• Lipopolysaccharides (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• MicroRNAs (antagonists & inhibitors, metabolism)
• NADPH Oxidases (metabolism)
• RAW 264.7 Cells
• RNA, Small Interfering (pharmacology)
• Reactive Oxygen Species (metabolism)