MicroRNAs and autoimmunity

Abstract

The role of microRNAs (miRNAs) in the regulation of many physiological and pathological processes has been intensely studied in recent years. Some miRNAs, such as miR-146a and miR-182, play a dominant role in the regulation of the innate and adaptive immune responses, respectively. Many miRNAs are reportedly deregulated in autoimmune diseases, but miR-146a in particular seems to be consistently altered. The overexpression or underexpression of miRNAs can influence specific targets and pathways, leading to autoimmune disease phenotypes, and this is supported also by some in vivo studies. Targeting miRNAs could represent a valid future therapeutic option for autoimmune diseases.

Figure 1. Aberrantly expressed miRNAs in SLE

Different cell types in SLE patients and lupus murine models are targeted by miRNAs with increased (left) or decreased (right) expression. MiR-126, miR-148a, and miR-21 modulate autoimmune-associated methylation sensitive genes in T cells, and miR-21 also stimulates the production of IL-10. MiR-155 and miR-15a are overexpressed in murine lupus models, causing Treg alterations and anti-dsDNA antibodies production by B cells, respectively. Decreased expression of miR-125a, miR-31, miR-142-3p/5p, and miR-23b induces the production of pro-inflammatory cytokines. MiR-146a is downregulated in SLE and it induces the hyperactivation of I-IFN pathway in peripheral blood mononuclear cells. Solid lines, overexpressed miRNAs (left); dotted lines, underexpressed miRNAs (right). References are shown in brackets.

Figure 2. Aberrantly expressed miRNAs in RA

The increased expression of miR-221/222, miR-323-3p, miR-203 (left) leads to arthritic/activated phenotype of synovial fibroblasts, while overexpression of miR-155 and miR-146a is associated with overproduction of inflammatory cytokines. Decreased expression of miR-34a*, miR-124a, miR-23b (right) causes different pro-inflammatory effects in joints of RA patients. Solid lines, overexpressed miRNAs (left); dotted lines, underexpressed miRNAs (right).

Figure 3. Examples of dominant miRNAs in immunity

Examples of dominant miRNAs that, after a specific stimulation, increase of >100 fold and induce a specific effect in the immune response. Panel A. miR-146a as a dominant miRNA in endotoxin tolerance. THP-1 monocytes stimulated with high-dose LPS at 1 μg/ml at time 0 produce a prominent TNF-α response that peaks at ~4-6 h. There are respective increases in both MyD88 pathway adaptors IRAK1 and TRAF6, which peak at 2-4 h and are documented targets of miR-146a. The miR-146a expression progressively increases about 100 fold starting at 2 h to down-regulate IRAK1/TRAF6 and continues to increase in the presence of LPS over a 3-day period. The high level of miR-146a maintains the LPS tolerance stage such that, when challenged with LPS again, it leads to a hypo-responsiveness state. Panel B. miR-182 as a dominant miRNA for adaptive immune response. The stimulation of different T cell populations (T_H1, T_H2 and T_H17) by IL-2 causes the strong overexpression (50-200 fold) of miR-182, with a peak at day 3. This miRNA downregulates its target Foxo1, causing the consequent T cell expansion.