Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis

Jingyi Li,Liyun Zou,Hongli Liu,Ying Wan,Yongfei Fang,Jinjun Zhang,Yuzhang Wu,Xiaolan Fu,Jinyu Zhang,Qiuye Guo,Jingbo Zhang,Liwei Lu

doi:10.1186/ar3006

Abstract

IntroductionIncreasing evidence indicates that microRNAs (miRNAs) play a critical role in the pathogenesis of inflammatory diseases. The aim of the study was to investigate the expression pattern and function of miRNAs in CD4+ T cells from patients with rheumatoid arthritis (RA).MethodsThe expression profile of miRNAs in CD4+ T cells from synovial fluid (SF) and peripheral blood of 33 RA patients was determined by microarray assay and validated by qRT-PCR analysis. The correlation between altered expression of miRNAs and cytokine levels was determined by linear regression analysis. The role of miR-146a overexpression in regulating T cell apoptosis was evaluated by flow cytometry. A genome-wide gene expression analysis was further performed to identify miR-146a-regulated genes in T cells.ResultsmiRNA expression profile analysis revealed that miR-146a expression was significantly upregulated while miR-363 and miR-498 were downregulated in CD4+ T cells of RA patients. The level of miR-146a expression was positively correlated with levels of tumor necrosis factor-alpha (TNF-α), and in vitro studies showed TNF-α upregulated miR-146a expression in T cells. Moreover, miR-146a overexpression was found to suppress Jurkat T cell apoptosis. Finally, transcriptome analysis of miR-146a overexpression in T cells identified Fas associated factor 1 (FAF1) as a miR-146a-regulated gene, which was critically involved in modulating T cell apoptosis.ConclusionsWe have detected increased miR-146a in CD4+ T cells of RA patients and its close correlation with TNF-α levels. Our findings that miR-146a overexpression suppresses T cell apoptosis indicate a role of miR-146a in RA pathogenesis and provide potential novel therapeutic targets.

Highlights

Increasing evidence indicates that microRNAs play a critical role in the pathogenesis of inflammatory diseases
Increased miR-146a expression in CD4+ T cell from synovial fluid (SF) and peripheral blood of rheumatoid arthritis (RA) patients The expression profiles of miRNAs in CD4+ T cells of SF from two RA patients were determined by miRNA microarray analysis
According to the results of microarray analysis, we focused on verifying the expression of those miRNAs whose expression levels were altered in both RA patients (Figure 1b)

Summary

Introduction

Increasing evidence indicates that microRNAs (miRNAs) play a critical role in the pathogenesis of inflammatory diseases. T cells isolated from joint tissue and synovial fluid (SF) show an activated and memory phenotype and appear to respond poorly to stimulation with mitogen or antigens in vitro [4,5] These T cells are unusually resistant to apoptosis in SF that contains a significant amount of proapoptotic factors such as bioactive FasL, TRAIL and TNF-α [6,7]. Studies on a murine model of proteoglycan-induced arthritis showed that CD4+ T cells failed to undergo apoptosis [8] All these findings from patients and animal models suggest that the inhibition of T cell death may result in the persistence and accumulation of T cells in synovium, as well as the accumulation of T cells in the periphery.

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