MicroRNA-146a is induced by inflammatory stimuli in airway epithelial cells and augments the anti-inflammatory effects of glucocorticoids

Abstract

BackgroundMicroRNAs (miRNAs) are emerging as central regulators of inflammation, but their role in asthma and airway epithelial cells is not well studied. Glucocorticoids are the cornerstone of therapy in asthma and other inflammatory disease, yet their mechanisms of action are not completely elucidated, and it is not clear whether miRNAs modulate their effects.ObjectiveWe aimed to identify miRNAs that regulate cytokine and chemokine expression in airway epithelial cells and whether these miRNAs are subject to the effects of glucocorticoids.Methods and resultsMicroRNAomic analyses of immortalized, normal human bronchial epithelial cells identified 7 miRNAs that were altered by inflammatory cytokine treatment and 22 that were regulated by glucocorticoids (n = 3 for each treatment condition). MiR-146a emerged as a central candidate, whose expression was induced by TNF-α and repressed by glucocorticoids. Its role as a candidate in asthmatic inflammation was supported by expression profiling in human asthmatics, which showed that plasma miR-146a expression was elevated in asthma and associated with measures related to worse asthma outcomes, including elevated blood eosinophil counts, higher asthma control questionnaire scores, and need for higher doses of inhaled glucocorticoids. However, transfection of miR-146a in A549 cells treated with TNF-α +/- glucocorticoids produced an anti-inflammatory effect and increased efficacy of glucocorticoids.ConclusionsWe propose a model whereby miR-146a is induced by inflammatory conditions as a feedback mechanism to limit inflammation. Exogenous administration of miR-146a augmented the effects of glucocorticoids and could be a novel therapeutic strategy to enhance efficacy of these medications.

Deducting MicroRNA-Mediated Changes Common in Bronchial Epithelial Cells of Asthma and Chronic Obstructive Pulmonary Disease—A Next-Generation Sequencing-Guided Bioinformatic Approach

“…In line with our finding, some studies showed that children with asthma had significantly higher plasma miR-146a level than healthy controls [32,33]. A recent study even showed that the increased plasma miR-146a level in asthmatics was associated with elevated blood eosinophil count, worse asthma control status, and requirement of higher doses of inhaled corticosteroids [34]. Similarly, increased miR-146a was found in the peripheral blood mononuclear cells from children with allergic rhinitis after allergen-specific immunotherapy [35].…”

“…Reduction of miR-146a was found in T cells from patients with severe asthma [36]. However, A549 cells transfected with miR-146a had increased response to glucocorticoids, suggesting that miR-146a might be induced by inflammatory condition and served as a feedback mechanism to limit inflammation [34]. In a study using the ovalbumin-induced asthmatic mice model, miR-146a inhibited the ovalbumin-induced airway hyper-responsiveness and the responses of the group 2 innate lymphoid cells [37].…”

Sulforaphane reduces intracellular survival of Staphylococcus aureus in macrophages through inhibition of JNK and p38 MAPK‑induced inflammation

“…The present study demonstrated that expression levels of miR-142-5p and miR-146a-5p are negatively regulated by SFN, suggesting their involvement in SFN-mediated decrease of cell apoptosis. miR-146a-5p expression levels are induced by inflammatory stimuli including TNF-α and IL-1β, and exert an anti-inflammatory effect by inhibiting pro-inflammatory genes such as IL-1 receptor associated kinase 1 and TNF receptor associated factor 6 in human adipocytes (48,49). We hypothesize that the lower than expected expression levels of miR-142-5p and miR-146a-5p observed in THP-1-derived macrophages infected by S. aureus may be due to the short incubation time (3 h after infection) in the experiment in the present study.…”

A Review of Macrophage MicroRNAs’ Role in Human Asthma

“…In another study, it was suggested that miRNA-146a could be used to boost the anti-inflammatory effects of glucocorticosteroids in steroid-insensitive asthmatics [88].…”

“…MiRNA-146a levels were reported to be increased in adults with asthma [27], and associated with indices related to worse asthma outcomes, including elevated blood eosinophil counts, higher asthma control questionnaire scores, and need for higher doses of ICS [88]. Overexpression of miRNA-146a in A549 human lung carcinoma cells combined with dexamethasone had greater anti-inflammatory effects than either alone, suggesting that miRNA-146a could be used to boost the anti-inflammatory effects of glucocorticosteroids in steroid-insensitive asthmatics [88].…”