title: 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.
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom.
authors.forename: Mariola
authors.initials: M
authors.lastname: Kurowska-Stolarska
authors.forename: Stefano
authors.initials: S
authors.lastname: Alivernini
authors.forename: Lucy E
authors.initials: LE
authors.lastname: Ballantine
authors.forename: Darren L
authors.initials: DL
authors.lastname: Asquith
authors.forename: Neal L
authors.initials: NL
authors.lastname: Millar
authors.forename: Derek S
authors.initials: DS
authors.lastname: Gilchrist
authors.forename: James
authors.initials: J
authors.lastname: Reilly
authors.forename: Michelle
authors.initials: M
authors.lastname: Ierna
authors.forename: Alasdair R
authors.initials: AR
authors.lastname: Fraser
authors.forename: Bartosz
authors.initials: B
authors.lastname: Stolarski
authors.forename: Charles
authors.initials: C
authors.lastname: McSharry
authors.forename: Axel J
authors.initials: AJ
authors.lastname: Hueber
authors.forename: Derek
authors.initials: D
authors.lastname: Baxter
authors.forename: John
authors.initials: J
authors.lastname: Hunter
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.forename: Foo Y
authors.initials: FY
authors.lastname: Liew
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001483:Base Sequence; D016022:Case-Control Studies; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D010003:Osteoarthritis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases