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Epigenetic regulation of inflammation by microRNAs in post-infectious bronchiolitis obliterans
Ruth P Duecker1, Ines De Mir Messa2, Silvija-Pera Jerkic1
1Division for Allergy, Pneumology and Cystic Fibrosis Department for Children and Adolescence Goethe University Frankfurt Germany.
Objectives:
Post-infectious bronchiolitis obliterans (PiBO) is a rare, chronic disease initiated by severe infection and followed by perpetuating inflammation and obliteration of the small airways. MicroRNAs (miRNAs) have been proposed to play a central role as epigenetic regulators, which control resolution and prevent the uncontrolled progress of inflammation. The aim of this study was to define biomarkers on the level of post-transcriptional gene regulation in order to characterise PiBO.
Methods:
A total of 39 patients with well-defined PiBO and 31 controls from two centres, Barcelona, Spain, and Frankfurt, Germany, were analysed by next-generation sequencing (NGS). The evaluation of the biological targets of the miRNAs was performed by pathway enrichment analysis and protein-protein interaction network analysis respectively.
Results:
Patients with PiBO had significantly lower lung function values and increased airway inflammation in induced sputum as indicated by total cell counts, neutrophils, IL-1β, IL-6, IL-8 and TGF-β compared to controls.Next-generation sequencing analysis revealed a total of 22 dysregulated miRNAs, which passed significance threshold for Padj ≤ 0.001 with 17 being upregulated and 5 being downregulated. Of these dysregulated miRNAs, miR-335-5p, miR-186-5p, miR-30b-5p and miR-30c-5p were further validated using qRT-PCR. Interestingly, these miRNAs are functionally implicated in cytokine-cytokine receptor interaction, TGF-β signalling and FoxO signalling pathway and significantly correlated with lung function values (FEV1).
Conclusion:
Our results demonstrate an aberrant miRNA expression profile in PiBO, which impacts pathways responsible for the regulation of inflammation and fibrosis. The defined miRNAs are useful biomarkers and should be assessed as potential target in the field of miRNA therapeutics.
Insights
Post-infectious bronchiolitis obliterans (PiBO) involves airway inflammation. This study identified specific microRNAs (miRNAs) linked to PiBO, suggesting their potential as diagnostic biomarkers and therapeutic targets.
Area of Science:
- Pulmonary Medicine
- Epigenetics
- Molecular Biology
Background:
- Post-infectious bronchiolitis obliterans (PiBO) is a rare, chronic airway disease following severe infection.
- MicroRNAs (miRNAs) are epigenetic regulators implicated in controlling inflammation and disease progression.
Purpose of the Study:
- To identify biomarkers at the post-transcriptional gene regulation level for characterizing PiBO.
- To investigate the role of miRNAs in the pathogenesis of PiBO.
Main Methods:
- Next-generation sequencing (NGS) was used to analyze miRNA expression in 39 PiBO patients and 31 controls.
- Pathway enrichment and protein-protein interaction network analyses were performed to evaluate miRNA targets.
- Quantitative reverse transcription PCR (qRT-PCR) validated specific miRNA dysregulations.
Main Results:
- PiBO patients exhibited reduced lung function and increased airway inflammation markers (neutrophils, IL-1β, IL-6, IL-8, TGF-β).
- NGS identified 22 significantly dysregulated miRNAs (17 upregulated, 5 downregulated) in PiBO patients.
- Four miRNAs (miR-335-5p, miR-186-5p, miR-30b-5p, miR-30c-5p) correlated with lung function (FEV1) and were involved in key signaling pathways.
Conclusions:
- Aberrant miRNA expression profiles are characteristic of PiBO, affecting inflammation and fibrosis pathways.
- The identified miRNAs serve as potential biomarkers for PiBO diagnosis.
- These miRNAs represent promising targets for future miRNA-based therapeutics in PiBO.
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