Abstract
Autophagy plays critical roles in airway inflammation and fibrosis-mediated airway remodeling and many factors including proinflammatory cytokines and inflammation related pathways are involved in the process. The aim of the present study was to examine the role of epithelial microRNAs (miRNAs) in autophagy-mediated airway remodeling and to identify the factors involved and the underlying mechanisms. Serum miR-34/449, inflammatory factors, and autophagy and fibrosis-related proteins were determined by real-time PCR, enzyme-linked immunosorbent assay and western blotting in 46 subjects with asthma and 10 controls and in the lung epithelial cell line BEAS-2B induced with IL-13 and treated with miRNA mimics. Luciferase assays were used to verify IGFBP-3 as a target of miR-34/449, and immunohistochemistry, immunofluorescence and co-immunoprecipitation were used in vitro and in vivo study. miR-34/449 were downregulated in patients with asthma in parallel with the upregulation of autophagy-related proteins. Proinflammatory factors and fibrosis-related proteins were significantly higher in asthma patients than in healthy controls. IL-13 induction promoted autophagy and upregulated miR-34/449 in BEAS-2B cells, and these effects were restored by IGFBP-3 silencing. miR-34/449 overexpression suppressed autophagy, decreased fibrosis, activated Akt, downregulated fibrosis-related factors, and downregulated proinflammatory cytokines and nuclear factor κB by targeting IGFBP-3. In vivo experiments showed that miR-34/449 overexpression was associated with Nur77 nuclear translocation and IGFBP-3 downregulation in parallel with decreased airway remodeling by decreased autophagy. miR-34/449 are potential biomarkers and therapeutic targets in asthma. miR-34/449 may contribute to airway inflammation and fibrosis by modulating IGFBP-3 mediated autophagy activation.
Highlights
Asthma is an inflammatory disease of the airways characterized by infiltration of inflammatory factors such as eosinophils, lymphocytes, and mast cells and reversible bronchoconstriction.[1]
The results showed that inhibition of Insulin growth factor binding protein-3 (IGFBP-3) mediated autophagy activation suppressed nuclear factor κB (NF-κB) expression, which can impact the expression of inflammation-related factors. (Figures 8a–e). miR-34/449 overexpression decreased the LC3-II/LC3-I ratio and downregulated Beclin-1, it had no significant effect on P62 expression in vivo (Figures 8f–i)
Asthma is an inflammatory disorder that involves several molecular and cellular processes, among which autophagy plays an important role in mediating allergic inflammation.[3] miRNAs are involved in inflammatory responses through the genes that they regulate, and several differentially expressed miRNAs have been identified in asthma.[13]
Summary
Asthma is an inflammatory disease of the airways characterized by infiltration of inflammatory factors such as eosinophils, lymphocytes, and mast cells and reversible bronchoconstriction.[1]. Insulin growth factor binding protein-3 (IGFBP-3), which modulates the activity of IGF and is involved in many human diseases, plays a role in the pathogenesis of asthma by modulating the tumor necrosis factor (TNF)-α induced expression of NF-κB signaling pathway molecules, suggesting that IGFBP-3 plays a role in airway inflammation and hyperresponsiveness through an IGF-independent pathway.[8] The NF-κB signaling pathway is activated in asthma, and Nur[77] ( known as NR4A1), a transcription factor that regulates many biological processes including inflammation and immunity, inhibits the NF-κB pathway in lung epithelial cells.[9] Translocation of Nur[77] from the nucleus to the cytosol or mitochondria results in apoptosis or autophagy.[10] Nur[77] deficiency resulted in increased mucus cell hyperplasia and airway inflammation in a murine model of ovalbumin (OVA)induced airway inflammation, suggesting that Nur[77] plays a protective role against airway inflammation. We examined the role of miR-34/449 and autophagy in airway inflammation and remodeling in a cohort of patients with asthma, in IL-13 induced lung epithelial cells in vitro, and in a murine model of OVA-induced airway inflammation in vivo and explored the underlying mechanisms
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