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.
Highlights
The airway epithelium is an immunologically active barrier in the lung, producing cytokines and other inflammatory and chemotactic mediators in response to antigen, pollutant and allergen exposure from the external environment [1]
We previously found that a majority of epithelial-derived cytokines that are susceptible to post-transcriptional regulation are not Th2-driven, but rather highly induced by tumor necrosis factor alpha (TNF-α), a general inflammatory stimulus and pathogenic cytokine in severe, corticosteroidrefractory asthma [9, 11,12,13,14]
Identification of miRNAs regulated by inflammatory stimuli or glucocorticoids We first sought to identify airway epithelial cell miRNAs that were altered by TNF- α and whether these effects were antagonized by glucocorticoids (GCs)
Summary
The airway epithelium is an immunologically active barrier in the lung, producing cytokines and other inflammatory and chemotactic mediators in response to antigen, pollutant and allergen exposure from the external environment [1]. The majority of asthmatic patients respond well to ICS, between a quarter and a third of individuals with poorly controlled asthma do not show improvement in pulmonary function despite treatment with high-dose, inhaled, or in some cases, oral corticosteroids [5, 6] This subset of ‘glucocorticoid-resistant’ or ‘steroid-insensitive’ patients often have the worst disease control, are at greatest risk for asthma morbidity and mortality, and contribute disproportionately to healthcare expenditure [7, 8]. A lack of alternative treatments for severe asthmatic and steroidinsensitive patients supports investigations into therapeutics that may improve the efficacy of existing ICS therapy The identification of such therapeutics relies on an evolving understanding of molecular mechanisms that regulate inflammation and glucocorticoid effects in the airway. 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
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