Kurowska-Stolarska, M; Alivernini, S; Ballantine, L E; Asquith, D L; Millar, N L; Gilchrist, D S; Reilly, J; Ierna, M; Fraser, A R; Stolarski, B; McSharry, C; Hueber, A J; Baxter, D; Hunter, J; Gay, S; Liew, F Y; McInnes, I B (2011). MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 108(27):11193-11198.
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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.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine|
|DDC:||610 Medicine & health|
|Deposited On:||12 Jul 2011 12:37|
|Last Modified:||27 Nov 2013 23:33|
|Publisher:||National Academy of Sciences|
|Free access at:||Publisher DOI. An embargo period may apply.|
|Citations:||Web of Science®. Times Cited: 88|
Scopus®. Citation Count: 101
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