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- Title
A microRNA-21–mediated SATB1/S100A9/NF-κB axis promotes chronic obstructive pulmonary disease pathogenesis.
- Authors
Kim, Richard Y.; Sunkara, Krishna P.; Bracke, Ken R.; Jarnicki, Andrew G.; Donovan, Chantal; Hsu, Alan C.; Ieni, Antonio; Beckett, Emma L.; Galvão, Izabela; Wijnant, Sara; Ricciardolo, Fabio LM.; Di Stefano, Antonino; Haw, Tatt Jhong; Liu, Gang; Ferguson, Angela L.; Palendira, Umamainthan; Wark, Peter A.; Conickx, Griet; Mestdagh, Pieter; Brusselle, Guy G.
- Abstract
MicroRNA-21 and COPD: Chronic obstructive pulmonary disease (COPD) is a progressively debilitating illness, and current therapies do not modify the decline in lung function seen over time. Here, Kim and colleagues investigated microRNAs in mice exposed to cigarette smoke, identifying miR-21 as being elevated during the progression of COPD. They confirmed this elevation in bronchial samples and lung tissues from patients with COPD. Cigarette smoke–exposed mice were treated with a miR-21–specific antagomir, lowering miR-21 expression, suppressing airway inflammation, and improving small airway fibrosis and lung function. Antagomir treatment restored special AT-rich sequence–binding protein 1 (SATB1) concentrations, leading to decreased S100A9 and NF-κB activity. This signaling axis may be targeted to develop more specific treatments for COPD. Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death worldwide. Inhalation of cigarette smoke (CS) is the major cause in developed countries. Current therapies have limited efficacy in controlling disease or halting its progression. Aberrant expression of microRNAs (miRNAs) is associated with lung disease, including COPD. We performed miRNA microarray analyses of the lungs of mice with CS-induced experimental COPD. miR-21 was the second highest up-regulated miRNA, particularly in airway epithelium and lung macrophages. Its expression in human lung tissue correlated with reduced lung function in COPD. Prophylactic and therapeutic treatment with a specific miR-21 inhibitor (Ant-21) inhibited CS-induced lung miR-21 expression in mice; suppressed airway macrophages, neutrophils, and lymphocytes; and improved lung function, as evidenced by decreased lung hysteresis, transpulmonary resistance, and tissue damping in mouse models of COPD. In silico analyses identified a potential miR-21/special AT-rich sequence–binding protein 1 (SATB1)/S100 calcium binding protein A9 (S100A9)/nuclear factor κB (NF-κB) axis, which was further investigated. CS exposure reduced lung SATB1 in a mouse model of COPD, whereas Ant-21 treatment restored SATB1 and reduced S100A9 expression and NF-κB activity. The beneficial effects of Ant-21 in mice were reversed by treatment with SATB1-targeting small interfering RNA. We have identified a pathogenic role for a miR-21/SATB1/S100A9/NF-κB axis in COPD and defined miR-21 as a therapeutic target for this disease.
- Subjects
LUNGS; CHRONIC obstructive pulmonary disease; SMALL interfering RNA; PATHOGENESIS; LABORATORY mice; PULMONARY fibrosis
- Publication
Science Translational Medicine, 2021, Vol 13, Issue 621, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aav7223