MicroRNA Regulation in Systemic Lupus Erythematosus Pathogenesis

Abstract

MicroRNAs (miRNAs) are endogenous small RNA molecules best known for their function in post-transcriptional gene regulation. Immunologically, miRNA regulates the differentiation and function of immune cells and its malfunction contributes to the development of various autoimmune diseases including systemic lupus erythematosus (SLE). Over the last decade, accumulating researches provide evidence for the connection between dysregulated miRNA network and autoimmunity. Interruption of miRNA biogenesis machinery contributes to the abnormal T and B cell development and particularly a reduced suppressive function of regulatory T cells, leading to systemic autoimmune diseases. Additionally, multiple factors under autoimmune conditions interfere with miRNA generation via key miRNA processing enzymes, thus further skewing the miRNA expression profile. Indeed, several independent miRNA profiling studies reported significant differences between SLE patients and healthy controls. Despite the lack of a consistent expression pattern on individual dysregulated miRNAs in SLE among these studies, the aberrant expression of distinct groups of miRNAs causes overlapping functional outcomes including perturbed type I interferon signalling cascade, DNA hypomethylation and hyperactivation of T and B cells. The impact of specific miRNA-mediated regulation on function of major immune cells in lupus is also discussed. Although research on the clinical application of miRNAs is still immature, through an integrated approach with advances in next generation sequencing, novel tools in bioinformatics database analysis and new in vitro and in vivo models for functional evaluation, the diagnostic and therapeutic potentials of miRNAs may bring to fruition in the future.

Keywords: Autoimmunity; MicroRNAs; Systemic Lupus Erythematosus.

Figure 1

Biogenesis of miRNA. MiRNA coding genes or the regions within introns of protein-coding genes are transcribed in the nucleus by RNA polymerase II. The transcription products are the hairpin-structured primary miRNAs (pri-miRNA) which will be further processed into precursor miRNA (pre-miRNA) by the microprocessor complex containing the Dorsha and DiGeorge Syndrome critical region 8 (DGCR8). These pre-miRNA will be transported into the cytoplasm by exportin 5 (XPO5), which the terminal loop will be excised and processed into a 18- to 24-nucleotide long duplex by Dicer. The RNA interfering silencing complex (RISC) will then unwind the miRNA duplex into single-stranded miRNA. While the single-stranded star form miRNA will be degraded rapidly, the other mature single-stranded miRNA will be directed to its complementary target mRNA. The target mRNA will be degraded if the complementarity is sufficient, while mRNA translation will be inhibited if complementarity is insufficient.