Role of MicroRNAs in the innate immune response to rhinovirus infection in asthma

Abstract

Asthma is one of the commonest chronic diseases worldwide and severe asthma sufferers experience recurrent exacerbations. Exacerbations are predominantly virus-induced and have been linked to defective interferon responses by airway immune and structural cells. Ascertaining the molecular mechanisms underlying this deficiency is a major research goal in order to identify new therapeutic targets.

We hypothesised that impaired interferon responses in severe asthma are caused by aberrations in microRNA expression in alveolar macrophages. MicroRNAs are non-coding RNA molecules that down-regulate gene expression. We identified and focused on 3 microRNAs predicted to target Toll-like receptor 7 (TLR7). We hypothesised that reduced expression of TLR7 would lead to reduced innate immune responses to the virus and that manipulating the expression of these microRNAs could restore the defective interferon response in asthmatic alveolar macrophages.

Alveolar macrophages were isolated from bronchoalveolar lavage from healthy and severe asthma subjects. Expression of microRNAs miR-150, -152 and -375 was increased and expression of TLR7reduced in alveolar macrophages from severe asthma subjects compared to healthy subjects. Using a TLR7- luciferase reporter construct we showed that the 3 microRNAs directly targeted the 3’UTR of TLR7 and operated synergistically to reduce its expression. Reduced TLR7 expression was association with impaired interferon responses to rhinovirus and imiquimod, a specific TLR7 agonist, and correlated inversely with number of disease exacerbations. Ex vivo knock-down of these microRNAs restored TLR7 expression with concomitant augmentation of virus-induced interferon production.

In conclusion, the results presented here show that increased expression of miR-150, miR-152 and miR-375 in severe asthma leads to reduced expression of TLR7 in alveolar macrophages and contributes to the impaired innate immune response to rhinovirus. This would certainly predispose the individual to more frequent and prolonged exacerbations due to reduced viral clearance by airway cells. Importantly we show that knock-down of these microRNAs in alveolar macrophages rescues the expression of interferon, providing a novel therapeutic target for the prevention and treatment of asthma exacerbations.

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