Abstract
BackgroundRecent reports have shown that microRNAs (miRNAs) regulate vital immunological processes and have emerged as key regulators of immune system development and function. Therefore, it is important to determine miRNA dysregulation and its pathogenic contribution in autoimmune diseases, an aspect not adequately addressed thus far.Methodology/Principal FindingsIn this study, we profiled miRNA expressions in splenic lymphocytes from three murine lupus models (MRL-lpr, B6-lpr and NZB/WF1) with different genetic background by miRNA microarray assays and Real-time RT-PCR. Despite the genetic differences among these three lupus stains, a common set of dysregulated miRNAs (miR-182-96-183 cluster, miR-31, and miR-155) was identified in splenocytes when compared with age-matched control mice. The association of these miRNAs with the disease was highlighted by our observation that this miRNA expression pattern was evident in NZB/W mice only at an age when lupus disease is manifested. Further, we have shown that the miRNA dysregulation in MRL-lpr mice was not simply due to the activation of splenocytes. By Real-time RT-PCR, we confirmed that these miRNAs were upregulated in both purified splenic B and T cells from MRL-lpr mice. miR-127 and miR-379, which were greatly upregulated in splenocytes from lpr mice, were moderately increased in diseased NZB/W mice. In addition, Real-time RT-PCR revealed that miR-146a, miR-101a, and miR-17-92 were also markedly upregulated in splenic T, but not B cells from MRL-lpr mice.Conclusions/SignificanceThe identification of common lupus disease-associated miRNAs now forms the basis for the further investigation of the pathogenic contribution of these miRNAs in autoimmune lupus, which will advance our knowledge of the role of miRNAs in autoimmunity. Given that miRNAs are conserved, with regard to both evolution and function, our observation of a common lupus disease-associated miRNA expression pattern in murine lupus models is likely to have significant pathogenic, diagnostic, and/or therapeutic implications in human lupus.
Highlights
Systemic lupus erythematosus (SLE) is a chronic, complex, and debilitating systemic autoimmune disease
MiRNAs are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. miRNAs usually bind to the 39 untranslated region (39UTR) of target mRNAs through partial sequence homology, which result in either translation inhibition or degradation of target message RNAs
In the present study, we identify a miRNA expression pattern in splenic lymphocytes that is common to all three lupus strains with different genetic background, and more importantly we demonstrate that this miRNA expression pattern is associated with lupus disease development
Summary
Systemic lupus erythematosus (SLE) is a chronic, complex, and debilitating systemic autoimmune disease. While there has been significant progress in the understanding of SLE genetics, which includes mapping of multiple SLE susceptibility loci/genes in the human and murine genome, to date no single or combination of structural gene defect has been identified as a principal pathogenic factor in inducing SLE [1,2,3]. Genetic factors are important in SLE susceptibility, attention has been shifted to the contribution of the epigenetic regulatory defects including abnormal DNA methylation, histone modification, and more recently miRNA regulation to lupus pathogenesis [2]. MiRNAs are small (about 22 nucleotides), non-coding RNAs that regulate gene expression at the post-transcriptional level. It is important to determine miRNA dysregulation and its pathogenic contribution in autoimmune diseases, an aspect not adequately addressed far
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