MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis

Abstract

MicroRNA (miRNA) species (miR) regulate mRNA translation and are implicated as mediators of disease pathology via coordinated regulation of molecular effector pathways. Unraveling miR disease-related activities will facilitate future therapeutic interventions. miR-155 recently has been identified with critical immune regulatory functions. Although detected in articular tissues, the functional role of miR-155 in inflammatory arthritis has not been defined. We report here that miR-155 is up-regulated in synovial membrane and synovial fluid (SF) macrophages from patients with rheumatoid arthritis (RA). The increased expression of miR-155 in SF CD14 + cells was associated with lower expression of the miR-155 target, Src homology 2-containing inositol phosphatase-1 (SHIP-1), an inhibitor of inflammation. Similarly, SHIP-1 expression was decreased in CD68 + cells in the synovial lining layer in RA patients as compared with osteoarthritis patients. Overexpression of miR-155 in PB CD14 + cells led to down-regulation of SHIP-1 and an increase in the production of proinflammatory cytokines. Conversely, inhibition of miR-155 in RA synovial CD14 + cells reduced TNF-α production. Finally, miR-155–deficient mice are resistant to collagen-induced arthritis, with profound suppression of antigen-specific Th17 cell and autoantibody responses and markedly reduced articular inflammation. Our data therefore identify a role of miR-155 in clinical and experimental arthritis and suggest that miR-155 may be an intriguing therapeutic target.

Micro-RNA in der Pathogenese rheumatischer Erkrankungen

“…In der Suche nach neuen therapeutischen Ansätzen haben wir uns deshalb in den letzten Jahren auch besonders den microRNAs (miR) zugewendet [3, 4]. So konnten wir zuerst zeigen, dass miR146a und miR155 in RASF und besonders miR155 auch in Monozyten stark exprimiert werden [5] und als proinflammatorischer Regulator in Arthritismodellen fungiert [6]. Wir konnten ferner nachweisen, dass miRs wie miR203 entscheidend die inflammatorischen Zytokine wie IL6 in RASF stimuliert und selbst durch Demethylierung induziert wird [7].…”

Pivotal role of Interleukin-10 on microRNA-155 expression in regulation of the monocyte response in hypothermia.

“…SHIP-1 is one of the main targets by which miRNA-155 increases the production of pro-inflammatory cytokines (139,145,197). As expected, SHIP-1 mRNA is strongly down-regulated upon activation of the TLR-pathway.…”

“…Early on, an association with TNF-a was observed. The causal link between increased miRNA-155 and increased TNF-a was subsequently demonstrated by several groups (139,145,147). However, miRNA-155 has also been shown to have anti-inflammatory properties by inhibiting the expression of MyD88, the central signaling protein of TLR-4, and TAB2, an important signaling molecule of the NF-KB and MAPK-pathway 80 (140,148).…”

“…Several microRNAs have been investigated and found to be important in the monocyte response (136)(137)(138)(139)(140)(141)(142)(143)(144)(145)(146). Figure 4 shows some of these microRNAs and their proposed targets.…”

“…We will focus on microRNA-155 in our research. Depending on the target protein, the microRNAs can either have a proinflammatory or anti-inflammatory action (139,140,145,147,148). MiRNA-155 and protein .…”