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Pulmonary microRNA profiles identify involvement of Creb1 and Sec14l3 in bronchial epithelial changes in allergic
Sabine Bartel1,2, Nikola Schulz2,3, Francesca Alessandrini4
1Early origins of chronic lung disease, Priority Area Asthma &Allergy, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany.
Abstract:
Asthma is highly prevalent, but current therapies cannot influence the chronic course of the disease. It is thus important to understand underlying early molecular events. In this study, we aimed to use microRNAs (miRNAs) - which are critical regulators of signaling cascades - to identify so far uncharacterized asthma pathogenesis pathways. Therefore, deregulation of miRNAs was assessed in whole lungs from mice with ovalbumin (OVA)-induced allergic airway inflammation (AAI). In silico predicted target genes were confirmed in reporter assays and in house-dust-mite (HDM) induced AAI and primary human bronchial epithelial cells (NHBE) cultured at the air-liquid interface. We identified and validated 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. Sec14-like 3 (Sec14l3) - a putative target of Creb1 - was down-regulated in both asthma models and in NHBE cells upon IL13 treatment, while it's expression correlated with ciliated cell development and decreased along with increasing goblet cell metaplasia. Finally, we propose that Creb1/Crtc1-3 and Sec14l3 could be important for early responses of the bronchial epithelium to Th2-stimuli. This study shows that miRNA profiles can be used to identify novel targets that would be overlooked in mRNA based strategies.
Insights
This study identifies novel molecular pathways in asthma pathogenesis using microRNAs (miRNAs). Researchers found that specific miRNAs target key proteins involved in allergic airway inflammation, offering new therapeutic targets for chronic asthma.
Area of Science:
- Molecular biology
- Immunology
- Respiratory medicine
Background:
- Asthma is a prevalent chronic respiratory disease with limited treatment options affecting its course.
- Understanding early molecular events in asthma pathogenesis is crucial for developing effective therapies.
- MicroRNAs (miRNAs) are key regulators of cellular signaling pathways with potential roles in disease development.
Purpose of the Study:
- To identify novel asthma pathogenesis pathways using miRNAs.
- To investigate the role of miRNA deregulation in allergic airway inflammation (AAI).
- To validate miRNA targets in relevant asthma models and human cells.
Main Methods:
- Assessed miRNA deregulation in mouse lungs with ovalbumin (OVA)-induced AAI.
- Confirmed in silico predicted miRNA targets using reporter assays.
- Validated findings in house-dust-mite (HDM)-induced AAI and human bronchial epithelial cells (NHBE).
Main Results:
- Identified and validated Creb1 and Crtc1-3 as targets of miR-17, miR-144, and miR-21.
- Found Sec14l3, a Creb1 target, downregulated in asthma models and IL13-treated NHBE cells.
- Observed Sec14l3 expression correlated with ciliated cell development and inversely with goblet cell metaplasia.
Conclusions:
- Creb1/Crtc1-3 and Sec14l3 are proposed as important in early bronchial epithelial responses to Th2 stimuli.
- miRNA profiling can uncover novel therapeutic targets missed by mRNA-based strategies.
- This research provides new insights into the molecular mechanisms underlying asthma.