MicroRNA-155 regulates monocyte chemokine and chemokine receptor expression in Rheumatoid Arthritis

Abstract

Objective. To test the hypothesis that miR-155 regulates monocyte migratory potential via modulation of chemokine and chemokine receptor expression in RA, and thereby is associated with disease activity. Methods. The miR-155 copy-numbers in monocytes from peripheral blood (PB) of healthy (n = 22), RA (n = 24) and RA SF (n = 11) were assessed by real time-PCR using synthetic miR-155 as a quantitative standard. To evaluate the functional impact of miR-155, human monocytes were transfected with control or miR-155 mimic, and the effect on transcript levels, and production of chemokines was evaluated by Taqman low-density arrays and multiplex assays. A comparative study evaluated constitutive chemokine receptor expression in miR-155−/− and wild-type murine (CD115 + Ly6C + Ly6G−) monocytes. Results. Compared with healthy monocytes, the miR-155 copy-number was higher in RA, peripheral blood (PB) and SF monocytes (PB P < 0.01, and SF P < 0.0001). The miR-155 copy-number in RA PB monocytes was higher in ACPA-positive compared with ACPA-negative patients (P = 0.033) and correlated (95% CI) with DAS28 (ESR), R = 0.728 (0.460, 0.874), and with tender, R = 0.631 (0.306, 0.824) and swollen, R = 0.503 (0.125, 0.753) joint counts. Enforced-expression of miR-155 in RA monocytes stimulated the production of CCL3, CCL4, CCL5 and CCL8; upregulated CCR7 expression; and downregulated CCR2. Conversely, miR155−/− monocytes showed downregulated CCR7 and upregulated CCR2 expression. Conclusion. Given the observed correlations with disease activity, these data provide strong evidence that miR-155 can contribute to RA pathogenesis by regulating chemokine production and pro-inflammatory chemokine receptor expression, thereby promoting inflammatory cell recruitment and retention in the RA synovium.

MicroRNA-155 contributes to enhanced resistance to apoptosis in monocytes from patients with rheumatoid arthritis

“…The changes in cytokine levels we detected were a direct consequence of mir-155 over-expression, as no other stimulus was provided to the cells. These findings are supported by a recent study that reported a mir-155 mediated increase in the receptors for many of these chemokines [33]. Although we cannot rule out the possibility that the increase in detected cytokines could be due to increased numbers of surviving cells, rather than increased production per cell, the resulting wide-ranging influence of the induced mediators suggests a role for mir-155 in monocyte/macrophage-driven inflammatory processes in RA.…”

MicroRNA 155 Contributes to Host Immunity against Leishmania donovani but Is Not Essential for Resolution of Infection

“…S1A to D in the supplemental material). These cytokines have been shown to play an important role in monocyte migration and recruitment to the site of inflammation in leishmaniasis (36,37) and other diseases, such as HIV (38), rheumatoid arthritis, and atherosclerosis (39,40). Not surprisingly, chemical inhibition of CCR2 resulted in a reduction of parasitic burdens in L. donovani-infected miR155KO mice.…”

Failed Downregulation of Circulating MicroRNA-155 in the Early Phase after ST Elevation Myocardial Infarction Is Associated with Adverse Left Ventricular Remodeling

“…Further, proinflammatory effects of microRNA-155 were observed in monocytes. Transfection of monocyte cultures with microRNA-155 mimic led to increased proinflammatory cytokine and chemokine production and expression of the chemokine receptor CCR7, whereas IL-10 secretion and CCR2 expression were decreased [13,14]. These effects of microRNA-155 in monocytes and macrophages were attributed, at least in part, to a decreased repression of the suppressor of cytokine signaling-1 and SH2-containing inositol-5′-phosphatase 1, potent inhibitors of inflammation [5,6,13].…”