Abstract
BackgroundMicroRNA (miRNA) control key elements of mRNA stability and likely contribute to the dysregulated lung gene expression observed in systemic sclerosis associated interstitial lung disease (SSc-ILD). We analyzed the miRNA gene expression of tissue and cells from patients with SSc-ILD. A chronic lung fibrotic murine model was used.MethodsRNA was isolated from lung tissue of 12 patients with SSc-ILD and 5 controls. High-resolution computed tomography (HRCT) was performed at baseline and 2–3 years after treatment. Lung fibroblasts and peripheral blood mononuclear cells (PBMC) were isolated from healthy controls and patients with SSc-ILD. miRNA and mRNA were analyzed by microarray, quantitative polymerase chain reaction, and/or Nanostring; pathway analysis was performed by DNA Intelligent Analysis (DIANA)-miRPath v2.0 software. Wild-type and miR-155 deficient (miR-155ko) mice were exposed to bleomycin.ResultsLung miRNA microarray data distinguished patients with SSc-ILD from healthy controls with 185 miRNA differentially expressed (q < 0.25). DIANA-miRPath revealed 57 Kyoto Encyclopedia of Genes and Genomes pathways related to the most dysregulated miRNA. miR-155 and miR-143 were strongly correlated with progression of the HRCT score. Lung fibroblasts only mildly expressed miR-155/miR-21 after several stimuli. miR-155 PBMC expression strongly correlated with lung function tests in SSc-ILD. miR-155ko mice developed milder lung fibrosis, survived longer, and weaker lung induction of several genes after bleomycin exposure compared to wild-type mice.ConclusionsmiRNA are dysregulated in the lungs and PBMC of patients with SSc-ILD. Based on mRNA-miRNA interaction analysis and pathway tools, miRNA may play a role in the progression of the disease. Our findings suggest that targeting miR-155 might provide a novel therapeutic strategy for SSc-ILD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1054-6) contains supplementary material, which is available to authorized users.
Highlights
MicroRNA control key elements of messenger RNA (mRNA) stability and likely contribute to the dysregulated lung gene expression observed in systemic sclerosis associated interstitial lung disease (SSc-ILD)
Using mRNA expression analysis of lung tissue in a prospective cohort of patients with Systemic sclerosis (SSc)-ILD, we recently described immune activation pathways and upregulated transforming growth factor-β (TGFβ)-induced signature genes associated with progressive lung fibrosis [6]
Most patients with SSc-ILD developed progressive disease based on the FibMax, with a mean baseline score of 6.88 ± 4.47 compared to 12.76 ± 6.59 after treatment; p = 0.006
Summary
MicroRNA (miRNA) control key elements of mRNA stability and likely contribute to the dysregulated lung gene expression observed in systemic sclerosis associated interstitial lung disease (SSc-ILD). We analyzed the miRNA gene expression of tissue and cells from patients with SSc-ILD. The prevalence of SSc-ILD is high and approximately 15–30 % of patients will progress to severe lung fibrosis. Distinguishing those who will progress from those who will have slow or stable. MicroRNA (miRNA) are small RNA that are of vital importance in regulating gene expression within cells, having critical roles in innate and adaptive immunity in general [7]. Disease-associated miRNA represent a new class of therapeutic targets
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