MicroRNA in systemic lupus erythematosus

Introduction

MicroRNAs (miRNAs) have been found as endogenous small noncoding RNAs that fine-tune cellular gene expression and regulate physiological functions. miRNAs are involved in controlling immune cell development and regulating innate and adaptive immunity in both physiological and pathological conditions. Abnormal miRNA expression has been documented in systemic lupus erythematosus (SLE). Functional studies illustrate various mechanisms for dysregulated miRNAs in the pathogenesis of SLE. Studies on miRNA expression in peripheral blood cells, body fluid, and target tissues of SLE patients have revealed unique miRNA signatures and its association with disease activity and organ damage of SLE, which indicates miRNAs could be used as specific biomarkers for diagnosing SLE and assessing disease activity. Here, we summarize our current knowledge about the cellular and molecular mechanisms possibly used by miRNAs in the pathogenesis of SLE, and the future applications of miRNAs as biomarkers and therapeutic targets in the management of SLE.

The biology of miRNAs

A large proportion of miRNA genes are located within the intronic regions of a genome, with a few located in exonic regions. RNA polymerase II is responsible for the transcription of most miRNA genes. After transcription, the primary transcripts of miRNA genes (pri-miRNA) undergo complex processing, the detailed steps of which are reviewed elsewhere. Briefly, pri-miRNAs are cleaved by Drosha in the nucleus, and small hairpin RNAs (pre-miRNA) are released and exported to the cytoplasm by Exportin 5. In the cytoplasm, Dicer dices the pre-miRNA into a ∼22nt long duplex RNA containing two mature miRNA strands. Finally, one of the two strands are incorporated into the RNA-induced silencing complex (RISC), which contains a member of the Argonaut (Ago) protein family as a functional core. The transcriptional regulation of the expression of miRNA confers them with a cell-type specific and spatiotemporal expression patterns. Because of their complicated maturation process, post-transcriptional regulation by accessory factors (e.g., DGCR8, DDX5, TRBP) in the miRNA processing pathway fine-tunes the exact expression level of miRNA in specific cells.

By base-pairing of their seed region to the 3’UTR of a target mRNA, in some cases the coding region of the target mRNA, mature miRNAs can direct RISC to its targets and thus destabilize or cause translational inhibition of mRNAs. The nature of miRNA’s targeting strategy endows each mature miRNA with the ability to target multiple different mRNAs. Furthermore, a particular mRNA can be bound by multiple miRNAs, which regulate the expression of this same gene expression in concert. Similar to miRNA biogenesis, the function of miRNA can be affected by many protein factors. Therefore, by fine-tuning gene expression, miRNAs function as key regulators in immune system, and abnormal expression or dysfunction of miRNAs were found to be responsible for many autoimmune diseases, including SLE.

Role of miRNAs in SLE

The original discovery that linked the miRNA machinery to SLE was that certain autoantibodies in the sera of lupus patients can target epitopes of the key components of the miRNA pathway, such as GW182 and Ago2. The miRNA expression profiles of lupus patients and mouse models revealed that miRNAs are relevant to the pathogenesis of SLE . Investigations into the functions of abnormally expressed miRNAs have shed light on the mechanisms involved in the development of SLE ( Fig. 30.1 ).