Increased adenosine-to-inosine RNA editing in rheumatoid arthritis

Nikolaos I Vlachogiannis, Aikaterini Gatsiou, Domenico Alessandro Silvestris, Kimon Stamatelopoulos, Maria G Tektonidou, Angela Gallo, Petros P Sfikakis, Konstantinos Stellos

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Abstract

OBJECTIVE: Adenosine-to-inosine (A-to-I) RNA editing of Alu retroelements is a primate-specific mechanism mediated by adenosine deaminases acting on RNA (ADARs) that diversifies transcriptome by changing selected nucleotides in RNA molecules. We tested the hypothesis that A-to-I RNA editing is altered in rheumatoid arthritis (RA).

METHODS: Synovium expression analysis of ADAR1 was investigated in 152 RA patients and 50 controls. Peripheral blood mononuclear cells derived from 14 healthy subjects and 19 patients with active RA at baseline and after 12-week treatment were examined for ADAR1p150 and ADAR1p110 isoform expression by RT-qPCR. RNA editing activity was analysed by AluSx+ Sanger-sequencing of cathepsin S, an extracellular matrix degradation enzyme involved in antigen presentation.

RESULTS: ADAR1 was significantly over-expressed in RA synovium regardless of disease duration. Similarly, ADAR1p150 isoform expression was significantly increased in the blood of active RA patients. Individual nucleotide analysis revealed that A-to-I RNA editing rate was also significantly increased in RA patients. Both baseline ADAR1p150 expression and individual adenosine RNA editing rate of cathepsin S AluSx+ decreased after treatment only in those patients with good clinical response. Upregulation of the expression and/or activity of the RNA editing machinery were associated with a higher expression of edited Alu-enriched genes including cathepsin S and TNF receptor-associated factors 1,2,3 and 5.

CONCLUSION: A previously unrecognized regulation and role of ADAR1p150-mediated A-to-I RNA editing in post-transcriptional control in RA underpins therapeutic response and fuels inflammatory gene expression, thus representing an interesting therapeutic target.

Original languageEnglish
Pages (from-to)102329
JournalJournal of Autoimmunity
DOIs
Publication statusE-pub ahead of print - Sep 4 2019

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Vlachogiannis, N. I., Gatsiou, A., Silvestris, D. A., Stamatelopoulos, K., Tektonidou, M. G., Gallo, A., Sfikakis, P. P., & Stellos, K. (2019). Increased adenosine-to-inosine RNA editing in rheumatoid arthritis. Journal of Autoimmunity, 102329. https://doi.org/10.1016/j.jaut.2019.102329