Abstract
MicroRNAs markedly affect the immune system, and have a relevant role in CVD and autoimmune diseases. Yet, no study has analyzed their involvement in atherothrombosis related to APS and SLE patients. This study intended to: 1) identify and characterize microRNAs linked to CVD in APS and SLE; 2) assess the effects of specific autoantibodies. Six microRNAs, involved in atherothrombosis development, were quantified in purified leukocytes from 23 APS and 64 SLE patients, and 56 healthy donors. Levels of microRNAs in neutrophils were lower in APS and SLE than in healthy donors. Gene and protein expression of miRNA biogenesis-related molecules were also reduced. Accordingly, more than 75% of identified miRNAs by miRNA profiling were underexpressed. In monocytes, miR124a and -125a were low, while miR-146a and miR-155 appeared elevated. Altered microRNAs’ expression was linked to autoimmunity, thrombosis, early atherosclerosis, and oxidative stress in both pathologies. In vitro treatment of neutrophils, monocytes, and ECs with aPL-IgG or anti-dsDNA-IgG antibodies deregulated microRNAs expression, and decreased miRNA biogenesis-related proteins. Monocyte transfections with pre-miR-124a and/or -125a caused reduction in atherothrombosis-related target molecules. In conclusion, microRNA biogenesis, significantly altered in neutrophils of APS and SLE patients, is associated to their atherothrombotic status, further modulated by specific autoantibodies.
Highlights
On the other hand, the immunologic hallmarks of lupus are autoantibodies against nuclear proteins and anti-double-stranded DNA, so that anti-dsDNA titres correlate with disease activity and are associated with specific tissue damage[7,8]
Potential mRNA targets involved in processes such as atherothrombosis, immune response, oxidative stress
The present study demonstrated, for the first time, the altered expression of a number of miRNAs directly involved in atherothrombosis, and their modulation by effect of specific autoantibodies in both pathologies
Summary
The immunologic hallmarks of lupus are autoantibodies against nuclear proteins and anti-double-stranded DNA, so that anti-dsDNA titres correlate with disease activity and are associated with specific tissue damage[7,8]. Epigenetics, which comprises DNA methylation, histone modifications, and microRNA (miRNA) activity, is providing new directions linking genomics and environmental factors[17]. A number of works have analyzed the expression profile of miRNAs in peripheral blood cells, biological fluids, and tissues of patients with SLE. These works have shown that differential expression of multiple miRNAs seems to contribute to SLE pathogenesis, by regulating the type I interferon pathway, inflammatory cytokine expression, DNA methylation in T cells and local tissue inflammation (i.e. miR-15, miR-21, miR-31, miR-125a, miR142, miR146a, miR-155, and miR-181, among others)[21].
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