Toll-like receptor 7 is reduced in severe asthma and linked to altered microRNA profile

Abstract

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

OBJECTIVES:We investigated the hypothesis that reduced toll-like receptor (TLR) 7-derived signalling was driving the impaired interferon responses to rhinovirus by asthmatic alveolar macrophages (AMs) and molecular mechanisms underlying this deficiency were explored.

METHODS:AMs were recovered from bronchoalveolar lavage from healthy and severe asthma subjects. Expression of pattern-recognition receptors and microRNAs was evaluated by quantitative PCR and western blotting. A TLR7-luciferase reporter construct was created to evaluate binding of microRNAs to the 3'UTR of TLR7. Interferon production was measured by quantitative PCR and ELISA.

MEASUREMENTS AND MAIN RESULTS:The expression of TLR7 was significantly reduced in severe asthma AMs and was associated with reduced rhinovirus and imiquimod-induced interferon responses by these cells compared to healthy AMs. Severe asthma AMs also expressed increased levels of 3 microRNAs that we showed are able to directly reduce TLR7 expression. Ex vivo knock-down of these microRNAs restored TLR7 expression with concomitant augmentation of virus-induced interferon production.

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Identifiers

ORCID for Tilman Sanchez-Elsner: orcid.org/0000-0003-1915-2410

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