MicroRNAs (miRNA) are regulatory molecules that are increasingly implicated in transcriptional dysregulation associated with disease [
58,
59]. These are short (25 nucleotide) single-stranded non-coding RNA molecules that are processed from primary transcripts into stem-loop-stem structures and finally to functional single stranded RNA. This processed miRNA is complementary to a section of the target mRNA molecule, and will thus bind to and inhibit mRNA translation or initiate mRNA degradation (reviewed in [
60]). miRNA molecules regulate transcriptional networks in this way, with central roles in some cancers, cell development, inflammatory response and neurodegenerative disorders [
61‐
63]. The role of miRNA molecules in regulation of innate and adaptive immunity and autoimmunity has been reviewed extensively; and pertinent to the predominance of SLE (and other autoimmune diseases) in women, the regulation of immune system miRNAs by estrogen is also discussed [
59,
64].
In 2007, Dai et al. [
65] examined miRNA expression in peripheral blood mononuclear cells (PBMC) from 23 SLE patients compared to 10 healthy controls, indentifying seven consistently downregulated miRNAs in the disease state (miR-196a, miR-17-5p, miR-409-3p, miR-141, miR-383, miR-112 and miR-184), and nine upregulated miRNAs (miR-189, miR-61, miR-78, miR-21, miR-142-3p, miR-342, miR-299-3p, miR-198 and miR-298). In further studies on a subset of SLE patients, 36 upregulated and 30 downregulated miRNAs were identified in lupus nephritis (LN) patients compared to controls [
66]; and 29 and 50 differentially expressed miRNAs were found in African American and European American LN patients respectively [
67]. Further studies identified MiR-148a and MiR-21 as key microRNA molecules in lupus, with a role for both in DNA hypomethylation in the disease state [
68]. MiR-21 is again implicated in SLE, with a proposed role in T-cell response through regulation of PDCD4 [
69]. MiRNA-126 contributes to SLE by targeting DNA methylation [
70], and downregulation of miR-181-a has been associated with paediatric cases of SLE [
71]. An assay of miRNA-146a in PBMCs shows downregulation in SLE patients in two independent studies [
72,
73], and underexpression of this microRNA may underlie SLE through dysregulation of the type 1 interferon pathway [
73]. Recently, a SNP in the promoter of miR-146a was shown to decrease binding of the transcriptional factor Ets1 with concomitant decreased expression of the microRNA molecule. This may in turn cause upregulation of the type I IFN pathway, as seen in these patients [
53]. Decreased levels of miR-146a (and miR-155) in serum from SLE patients has been shown in a further study [
74], and the level of miR-155 is shown to be downregulated in regulatory T-cells from SLE patients [
75].
The type of microRNA dysregulation associated with SLE can also be indirect, for example Divekar et al. [
75] also show downregulation of gene expression for Dicer in regulatory T-cells from SLE patients. Dicer is the endoribonuclease that processes precursor microRNA molecules to generate functional microRNAs (described in [
76]), suggesting that the milieu of active microRNA molecules may generally be altered in regulatory T-cells from SLE patients due to changes in miRNA processing. In another study, Hikami et al. [
77] show that in a cohort of SLE patients, a disease-associated polymorphism in the 3’-untranslated region of the
SPI1 gene falls in a binding region for miR-569.