SEC14-like 3 is decreased in airway ciliated cells in experimental and paediatric asthma.

Abstract

Background: Asthma is the most common chronic disease in children leading to respiratory dysfunction in adults if not identified correctly. Therefore, there is an unmet clinical need to find novel treatment targets for asthma pathogenesis.   Objective: miRNA profiles were used to identify dysregulated signalling pathways in asthma as they are critical regulators of key molecules.   Methods: Whole lung microRNAs were identified in mice with ovalbumin (OVA)-induced allergic inflammation by qualitative and quantitative microarrays. Target mRNAs, identified by in silico analysis were validated using reporter assays. miRNAs and their targets were validated in house-dust-mite (HDM) induced asthma, primary normal human bronchial epithelial (NHBE) cells, and in nasal brushings from asthmatic children and controls.   Results: We identified the transcription factor cAMP-responsive element binding protein (CREB1) and its transcriptional co-activators (CRTC1 – 3) as targets of miR-17, miR-144, and miR-21 in vitro and ex vivo. A predicted CREB1 downstream target SEC14-like 3(SEC14l3) was down-regulated in two asthma models (OVA and HDM), was associated with ciliated cells in NHBE cultures and its expression was decreased by IL-13. In asthmatic children the three miRNAs were increased in nasal epithelial cells compared to healthy controls, while SEC14l3 expression was reduced.   Conclusion: By using altered miRNA profiles in experimental asthma we identified a so far non-characterized CREB1/CRTC-SEC14l3 axis that might be relevant for experimental and paediatric asthma