A microRNA-21-mediated SATB1/S100A9/NF-κB axis promotes chronic obstructive pulmonary disease pathogenesis

Richard Y Kim, Krishna P Sunkara, Ken R Bracke, Andrew G Jarnicki, Chantal Donovan, Alan C Hsu, Antonio Ieni, Emma L Beckett, Izabela Galvão, Sara Wijnant, Fabio Lm Ricciardolo, Antonino Di Stefano, Tatt Jhong Haw, Gang Liu, Angela L Ferguson, Umamainthan Palendira, Peter A Wark, Griet Conickx, Pieter Mestdagh, Guy G BrusselleGaetano Caramori, Paul S Foster, Jay C Horvat, Philip M Hansbro

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numbereaav7223
JournalScience Translational Medicine
Volume13
Issue number621
DOIs
Publication statusPublished - Nov 24 2021

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