Decreased expression of miR-146a and miR-155 contributes to an abnormal Treg phenotype in patients with rheumatoid arthritis

Abstract

ObjectivesMicroRNAs (miRNAs) have been implicated in the pathogenesis of autoimmune diseases, not least for their critical role in the regulation of regulatory T cell (Treg) function. Deregulated expression of miR-146a and miR-155 has been associated with rheumatoid arthritis (RA). We therefore investigated miR-146a and miR-155 expression in Tregs of patients with RA and their possible impact on Treg function and disease activity.MethodsExpression of miR-146a and miR-155 was assessed in RA patients and controls. MiRNA expression was correlated with disease activity and expression of target genes. Interference with biological activity of miRNAs was evaluated in functional Treg assays.ResultsDiminished upregulation of miR-146a and miR-155 in response to T cell stimulation was found in Tregs of RA patients. Diminution of miR-146a expression was observed in particular in patients with active disease, and correlated with joint inflammation. In patients with active RA, Tregs demonstrated a pro-inflammatory phenotype characterised by inflammatory cytokine expression. This was due to an augmented expression and activation of signal transducer and activator transcription 1 (STAT1), a direct target of miR-146a.ConclusionsOur results suggest that in RA miR-146a facilitates a pro-inflammatory phenotype of Tregs via increased STAT1 activation, and contributes thereby to RA pathogenesis.

Impaired regulatory T cell function in autoimmune diseases: are microRNAs the culprits?

“…[9][10][11][12] A recent report by Alla Skapenko and colleagues suggests that dysregulated miRNA expression in Tregs contributes to impaired Treg functions in RA (Figure 1). 13 MiRNAs (such as miR-146a, miR-155, miR-21, miR-142-3p, and miR-31) and miRNA-processing enzymes (Dicer and Drosha) are directly or indirectly linked to lymphocyte differentiation and function, including Tregs. 6,[13][14][15] The data obtained by Zhang et al suggest that miR-31 negatively regulates the generation of peripherally derived Tregs by inhibiting retinoic acid-inducible protein 3 (Gprc5a; Figure 1).…”

“…13 MiRNAs (such as miR-146a, miR-155, miR-21, miR-142-3p, and miR-31) and miRNA-processing enzymes (Dicer and Drosha) are directly or indirectly linked to lymphocyte differentiation and function, including Tregs. 6,[13][14][15] The data obtained by Zhang et al suggest that miR-31 negatively regulates the generation of peripherally derived Tregs by inhibiting retinoic acid-inducible protein 3 (Gprc5a; Figure 1). In an experimental autoimmune encephalomyelitis (EAE) model, miR-31 expression was upregulated in splenocytes and pathogenic T-cells.…”

“…6 The dysregulated expression of miR-146a and miR-155 is frequently reported in RA, and hence Alla Skapenko and colleagues aimed to investigate the regulation of miR-146a and miR-155 in the Tregs of patients with RA and their regulation of Treg functions and disease activity. 13 By using freshly isolated peripheral blood mononuclear cells from RA patients and healthy donors, the authors first explored the basal levels of miR146a and miR-155 in CD25 1 Tregs and CD25 2 non-Tregs. Further, both cell populations were stimulated for 24 and 48 h using anti-CD3/CD28 monoclonal antibodies.…”

“…For instance, RA patients with lower disease activity expressed higher miR-146a in Tregs, and vice versa. 13 The expression levels of miR-146a and miR-155 are positively regulated by the nuclear factor kappa B (NF-kB) pathway. However, these miRNAs control the NFkB pathway in a negative feedback loop.…”

“…Using gene expression-based analysis of IRAK1, TRAF6, and IKKe in the Tregs of RA patients, they observed that there was no correlation between the miR-146a and miR-155 levels and the expression of NF-kB pathway molecules. 13 Furthermore, the authors also analyzed the expression of two additional genes, STAT1 and SOCS1, that are known targets of miR-146a and miR-155, respectively. They determined that upon T-cell antigen receptor stimulation, STAT1, and SOCS1 expression levels are upregulated.…”