MicroRNA miR-24-3p reduces DNA damage responses, apoptosis, and susceptibility to chronic obstructive pulmonary disease

Jessica Nouws,Qile Dai,Maor Sauler,Xiting Yan,Willy Roque,Clemente J Britto,Maurizio Chioccioli,Eric Finnemore,Feng Wan,Veronique Neumeister,Åsa M Wheelock,Naftali Kaminski,C Magnus Sköld ,Chuanxing Li ,Isabel Bazán ,José L Gómez ,Patricia Lee ,Sojin Kim ,Ranjit S Bindra ,Joann B Sweasy

doi:10.1172/jci.insight.134218

Abstract

The pathogenesis of chronic obstructive pulmonary disease (COPD) involves aberrant responses to cellular stress caused by chronic cigarette smoke (CS) exposure. However, not all smokers develop COPD and the critical mechanisms that regulate cellular stress responses to increase COPD susceptibility are not understood. Because microRNAs are well-known regulators of cellular stress responses, we evaluated microRNA expression arrays performed on distal parenchymal lung tissue samples from 172 subjects with and without COPD. We identified miR-24-3p as the microRNA that best correlated with radiographic emphysema and validated this finding in multiple cohorts. In a CS exposure mouse model, inhibition of miR-24-3p increased susceptibility to apoptosis, including alveolar type II epithelial cell apoptosis, and emphysema severity. In lung epithelial cells, miR-24-3p suppressed apoptosis through the BH3-only protein BIM and suppressed homology-directed DNA repair and the DNA repair protein BRCA1. Finally, we found BIM and BRCA1 were increased in COPD lung tissue, and BIM and BRCA1 expression inversely correlated with miR-24-3p. We concluded that miR-24-3p, a regulator of the cellular response to DNA damage, is decreased in COPD, and decreased miR-24-3p increases susceptibility to emphysema through increased BIM and apoptosis.

Highlights

Chronic obstructive pulmonary disease (COPD) is a leading cause of global mortality and is characterized by persistent airflow limitation due to small airway disease and emphysema [1]
We analyzed microRNA profiles of lung tissue samples from subjects with and without chronic obstructive pulmonary disease (COPD) and found miR-24-3p was decreased in COPD and inversely correlated with disease severity (FEV1 percent predicted and radiographic emphysema)
We demonstrated that miR-24-3p inhibited apoptosis and homologous recombination (HR), and miR-24-3p inhibited the proapoptotic protein BIM and HR protein BRCA1

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a leading cause of global mortality and is characterized by persistent airflow limitation due to small airway disease and emphysema [1]. Individual differences in cellular stress responses to CS may be critical determinants of COPD severity, but there remains a limited understanding of the specific cellular responses that protect from or predispose individuals to disease progression [2, 3]. DNA damage is a well-described consequence of CS exposure, and growing evidence from genetic association studies and animal models of disease has suggested an important role for cellular responses to DNA damage in the pathobiology of COPD [4,5,6,7,8]. Cells maintain a network of intertwined signaling pathways collectively referred to as the DNA damage response (DDR) [9]. In the setting of severe DNA damage, the DDR activates specific programs such as cellular senescence or apoptosis.

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Results

Conclusion