MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD

Abstract

Reduced activity of histone deacetylase 2 (HDAC2) has been described in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms resulting in decreased expression of this important epigenetic modifier remain unknown. Here, we employed several in vitro experiments to address the role of microRNAs (miRNAs) on the regulation of HDAC2 in endothelial cells. Manipulation of miRNA levels in human pulmonary artery endothelial cells (HPAEC) was achieved by using electroporation with anti-miRNAs and miRNA mimics. Target prediction software identified miR-223 as a potential repressor of HDAC2. In subsequent stimulation experiments using inflammatory cytokines known to be increased in patients with COPD, miR-223 was found to be significantly induced. Functional analysis demonstrated that overexpression of miR-223 decreased HDAC2 expression and activity in HPAEC. Conversely, HDAC2 expression and activity was preserved in anti-miR-223-treated cells. Direct miRNAtarget interaction was confirmed by reporter gene assay. In a next step, reduced expression of HDAC2 was found to increase the levels of the chemokine fractalkine (CX3CL1). In vivo studies confirmed elevated expression levels of miR-223 in mice exposed to cigarette smoke and in emphysematous lung tissue from LPS-treated mice. Moreover, a significant inverse correlation of miR-223 and HDAC2 expression was found in two independent cohorts of COPD patients. These data emphasize that miR-223, the most prevalent miRNA in COPD, controls expression and activity of HDAC2 in pulmonary cells, which, in turn, might alter the expression profile of chemokines. This pathway provides a novel pathogenic link between dysregulated miRNA expression and epigenetic activity in COPD. KEY MESSAGES: Histone deacetylase 2 is directly targeted by miR-223. Levels of miR-223 are induced by interleukin-1 and tumor necrosis factor-. miR-223 controls the expression of fractalkine by targeting histone deacetylase 2. miR-223 levels are increased in COPD mouse models. miR-223 levels inversely correlate with HDAC2 expression in COPD patients. AbstractReduced activity of Histone Deacetylase 2 (HDAC2) has been described in patients with chronic obstructive pulmonary disease (COPD) but the mechanisms resulting in decreased expression of this important epigenetic modifier remain unknown. Here we employed several in vitro experiments to address the role of microRNAs (miRNAs) on the regulation of HDAC2 in endothelial cells. Manipulation of miRNA levels in human pulmonary artery endothelial cells (HPAEC) was achieved by using electroporation with anti-miRNAs and miRNA mimics.Target prediction software identified miR-223 as a potential repressor of HDAC2. In subsequent stimulation experiments using inflammatory cytokines known to be increased in patients with COPD miR-223 was found to be significantly induced. Functional analysis demonstrated that overexpression of miR-223 decreased HDAC2 expression and activity in HPAEC. Conversely, HDAC2 expression and activity was preserved i...

miRNAs in Lung Development and Diseases

“…In another set of experiments, miR-223 was suggested to induce CX3CL1 mRNA level by regulating histone deacetylase 2 in human pulmonary artery endothelial cells (HPAECs) [52]. In human lung tissues from two cohorts of COPD patients, there were negative correlations between miR-223 and histone deacetylase 2 levels [52]. In another study, miR-181c regulated CCN1, which was upregulated in the lung tissues of CS-exposed mice as well as COPD patients [53].…”

“…Furthermore, in a COPD rat model, cigarette smoke (CS) exposure elevated the concentrations of IFN-γ and TNF-α, increased the protein level of FAIM2, disrupted the lung architecture, and downregulated the level of miR-3202 [51]. In another set of experiments, miR-223 was suggested to induce CX3CL1 mRNA level by regulating histone deacetylase 2 in human pulmonary artery endothelial cells (HPAECs) [52]. In human lung tissues from two cohorts of COPD patients, there were negative correlations between miR-223 and histone deacetylase 2 levels [52].…”

MicroRNA miR-223 as regulator of innate immunity

“…60 The expression levels of miR-223 significantly Moreover, miR-223 was also detected in human pulmonary artery smooth muscle cells (HPASMC), normal human bronchial epithelial cells (NHBEC), and human pulmonary artery endothelial cells (HPAEC), in the later especially at higher levels after stimulation by IL-1 and TNF-. 63 The authors identified histone deacetylase 2 (HDAC2) as a direct target of miR-223 in HPAEC, and demonstrated the potential disease promoting function of miR-223 during chronic obstructive pulmonary diseases. These findings together showcase the diverse function of miR-223 in nonmyeloid cells.…”

The role of microRNAs in chronic respiratory disease: recent insights

“…Decreases in global micro-RNA abundance were also observed in populations of alveolar macrophages from cigarette smokers (Graff et al, 2012). In contrast, Leuenberger and colleagues found that miR-223 was upregulated in the lungs of smokers (Leuenberger et al, 2016). Increased miR-223 correlated with decreased Histone deacetylase 2 (HDAC2) expression, which led to elevated expression of a pro-inflammatory chemokine, CX3CL1.…”