Decreased expression of microRNA‐21 correlates with the imbalance of Th17 and Treg cells in patients with rheumatoid arthritis

Abstract

The imbalance of Th17/Treg cell populations has been suggested to be involved in the regulation of rheumatoid arthritis (RA) pathogenesis; however, the mechanism behind this phenomenon remains unclear. Recent studies have shown how microRNAs (miRNAs) are important regulators of immune responses and are involved in the development of a variety of inflammatory diseases, including RA. In this study, we demonstrated that the frequencies of CD3+CD4+IL-17+Th17 cells were significantly higher, and CD4+CD25+FOXP3+ Treg cells significantly lower in peripheral blood mononuclear cells from RA patients. Detection of cytokines from RA patients revealed an elevated panel of pro-inflammatory cytokines, including IL-17, IL-6, IL-1β, TNF-α and IL-22, which carry the inflammatory signature of RA and are crucial in the differentiation and maintenance of pathogenic Th17 cells and dysfunction of Treg cells. However, the level of miR-21 was significantly lower in RA patients, accompanied by the increase in STAT3 expression and activation, and decrease in STAT5/pSTAT5 protein and Foxp3 mRNA levels. Furthermore, lipopolysaccharide stimulation up-regulated miR-21 expression from healthy controls, but down-regulated miR-21 expression from RA patients. Therefore, we speculate that miR-21 may be part of a negative feedback loop in the normal setting. However, miR-21 levels decrease significantly in RA patients, suggesting that this feedback loop is dysregulated and may contribute to the imbalance of Th17 and Treg cells. MiR-21 may thus serve as a novel regulator in T-cell differentiation and homoeostasis, and provides a new therapeutic target for the treatment of RA.

Inhibition of cytokine response to TLR stimulation and alleviation of collagen‐induced arthritis in mice by Schistosoma japonicum peptide SJMHE1

“…Defects in CD4 + CD25 + Tregs have been observed in RA patients 16, and Treg plays a pivotal role in the regulation of auto‐reactive T‐cell activation in CIA 29. Our previous study demonstrated that SJMHE1 treatment increases CD4 + CD25 + Tregs in vivo and in vitro 11, as well as generates CD4 + CD25 + Tregs to suppress DTH responses 12.…”

Mesenchymal stem cells-derived exosomal microRNAs contribute to wound inflammation

“…The identification of novel upstream modulators or downstream targets of the IL-6/STAT3 pathway will provide insight into the involvement of altered miRNA expression in the progression of chronic inflammation. In RA patients, the expression levels of miR-21 were significantly lower and accompanied by increased STAT3 expression and activation (Dong et al, 2014). Moreover, Iliopoulos et al found that miR-21 and miR-181 are rapidly and dramatically regulated during cellular transformation.…”

miR-21 alters circulating Treg function in vascular disease—hope for restoring immunoregulatory responses in atherosclerosis?

“…miR-21 is known to be specifically expressed in the Treg subset (13) and promotes Treg differentiation by positively regulating expression of FoxP3 itself, the Treg-specific transcription factor. miR-21 also has the potential to positively regulate Treg activity by directly targeting a proposed negative regulator of TGF-β signaling, SMAD7 (14,15). In contrast, other studies have suggested that miR-21 in fact restrains Treg activity through intrinsic T-reg-specific mechanisms and limiting FOXP3 activity (16) or indirectly by promoting the activity of Th17 cells, whose pro-inflammatory nature counters Treg function (14).…”

“…For example, rheumatoid arthritis patients, characterized by chronic inflammation in synovial joints, display decreased serum miR-21 levels (15). This is associated with decreased Treg function and an increase in the number and activity of the Th17 subset, promoting chronic inflammation.…”