Source: International Congress 2014 – Novel epigenetic regulators for targeting via nanomedicine
Disease area: Airway diseases

Abstract

Virus-induced disease exacerbation is common in asthma and studies have shown that alveolar macrophages (AM) from asthmatics have reduced interferon (IFN) responses to rhinovirus (RV) infection. The mechanism behind this defect is unclear. We hypothesised that this deficiency is caused by a defect in the toll-like receptor (TLR) 7 pathway and is driven by aberrations in microRNA (miR) expression in AM. We identified and focused on 3 miRs predicted to target TLR7. We also hypothesised that manipulating the expression of these miRs could restore the defective IFN response in asthmatic AM.AM were isolated from bronchoalveolar lavage from healthy (HC) and severe asthma (SA) subjects. Expression of miRs and TLR7 was determined by qRT-PCR and western blotting. A TLR7-luciferase reporter construct was generated to confirm the bioinformatics predictions. AM were transfected with anti-miRs directed against the 3 miRs and treated with imiquimod (5ug/ml), a TLR7 agonist, or RV16. IFN (a and b) expression was determined after 24 hours using qRT-PCR and ELISA.Expression of miRs-150, -152 and -375 was increased and expression of TLR7 reduced in SA AM compared to HC. Using the TLR7-luciferase reporter construct we showed that the 3 miRs directly targeted the 3'UTR of TLR7. Compared to mock transfected AM, AM transfected with the 3 anti-miRs showed increased imiquimod and RV16-induced IFN expression.Reduced expression of TLR7 in SA AM is related to increased expression of miRs-150, -152 and -375. We propose this leads to impaired viral sensing by asthmatic AM and defective IFN response to RV. Knock-down of these miRs in AM rescues the expression of IFN, providing a novel target for therapy in asthma.

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Citations should be made in the following way:
H. Rupani, P. Dennison, N. Jayasekera, L. Lau, T. Sanchez-Elsner, P. Howarth (Southampton, United Kingdom). LSC 2014 abstract - Targeting of microRNAs can restore innate anti-viral response in asthma. Eur Respir J 2014; 44: Suppl. 58, 196

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