miR-155 in the progression of lung fibrosis in systemic sclerosis.

Abstract

BACKGROUND:

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. A chronic lung fibrotic murine model was used.

METHODS:

RNA 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.

RESULTS:

Lung 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.

CONCLUSIONS:

miRNA 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.

• Authors: Romy B Christmann, Alicia Wooten, Percival Sampaio-Barros, Claudia L Borges, Carlos R R Carvalho, Ronaldo A Kairalla, Carol Feghali-Bostwick, Jessica Ziemek, Yu Mei, Salma Goummih, Jiangning Tan, Diana Alvarez, Daniel J Kass, Mauricio Rojas, Thiago Lemos de Mattos, Edwin Parra, Giuseppina Stifano, Vera L Capelozzi, Robert W Simms, Robert Lafyatis
• Journal: Arthritis research & therapy (Arthritis Res Ther) Vol. 18 Issue 1 Pg. 155 (07 05 2016) ISSN: 1478-6362 [Electronic] England
• PMID: 27377409 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• MIRN155 microRNA, human
• MicroRNAs

Topics

• Animals
• Disease Models, Animal
• Disease Progression
• High-Throughput Nucleotide Sequencing
• Humans
• Lung Diseases, Interstitial (etiology, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• MicroRNAs (metabolism)
• Oligonucleotide Array Sequence Analysis
• Pulmonary Fibrosis (etiology, metabolism, pathology)
• Real-Time Polymerase Chain Reaction
• Scleroderma, Systemic (complications)