MicroRNA-34/449 targets IGFBP-3 and attenuates airway remodeling by suppressing Nur77-mediated autophagy

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.

Chrysophanol attenuates airway inflammation and remodeling through nuclear factor‐kappa B signaling pathway in asthma

“…Autophagy plays an essential role in pulmonary inflammation during asthma progress (Gu et al, ; J. N. Liu et al, ). Airway inflammation involves the induction of autophagy (Yin et al, ). Blockade of autophagy was demonstrated to attenuate asthmatic inflammation and airway remodeling (T. Liu et al, ).…”

40 YEARS OF IGF1: IGF-binding proteins

“…Within the nucleus, 365 IGFBP-3 interacted with receptors including RXR-α, PPAR-γ, the vitamin D receptor and Nur77, 366 leading to some of its effects on apoptosis, proliferation and differentiation. Nuclear IGFBP-3 also 367 had a role in DNA damage repair (Baxter 2015; Lin, et al 2014; Liu, et al 2000), and it activated 368 autophagy in bronchial epithelial cells by a mechanism involving translocation of the transcription 369 factor Nur77 from the nucleus (Yin, et al 2017). Further studies are required to enhance our 370 incomplete understanding of the cellular uptake and nuclear actions of IGFBP-3.…”

ncRNAs in Type-2 Immunity

“…Noteworthy, miR-449a/b/c are highly enriched in multi-ciliated cells of the human airway epithelium [123]. miR-34/449 family also target Igfbp-3, a transcript with an established role in modulating TNF-α induced expression of NF-κB [124], and recently suggested to modulate autophagy in the airway epithelium [125], possibly contributing to the pathogenesis of asthma. Due to its central role the homeostasis and differentiation of the epithelium, miR-449a/b/c knockdown results in the suppression of multiciliogenesis [123], and mice deficient for all three genomic loci of the miR-34/449 family die post-natal due to defective mucociliary clearance of the airways [120].…”

“…Due to its central role the homeostasis and differentiation of the epithelium, miR-449a/b/c knockdown results in the suppression of multiciliogenesis [123], and mice deficient for all three genomic loci of the miR-34/449 family die post-natal due to defective mucociliary clearance of the airways [120]. IL-13 signaling in human lung airway epithelial cell line BEAS-2B [125], or in primary human basal epithelial cells [114] caused a decrease in miR-34 and miR-449 expression as early as 3 days post exposure, consistent with the cytokine role in shaping cellular composition, reducing ciliated cells and promoting goblet cell hyperplasia (in Solberg et al microarray could not differentiate between miRNA isoforms). It is plausible that the downregulation of miR-34/449 by IL-13 contributes significantly to the pathogenic functions of IL-13.…”

“…It is plausible that the downregulation of miR-34/449 by IL-13 contributes significantly to the pathogenic functions of IL-13. Although the precise molecular mechanisms by which IL-13 modulates this family of miRNAs is unclear, it is tempting to speculate that this represents an opening for therapeutically intervention in allergic asthma [125]. A summary of miR-34 and miR-449 activity in epithelial cells (along with other miRNAs) is presented in Figure 5.…”