title: Promotion of Inflammatory Arthritis by Interferon Regulatory Factor 5 in a Mouse Model.
abstract: OBJECTIVE
  Polymorphisms in the transcription factor interferon regulatory factor 5 (IRF5) are associated with an increased risk of developing rheumatoid arthritis (RA). This study was undertaken to determine the role of IRF5 in a mouse model of arthritis development.
  
  
  METHODS
  K/BxN serum-transfer arthritis was induced in mice deficient in IRF5, or lacking IRF5 only in myeloid cells, and arthritis severity was evaluated. K/BxN arthritis was also induced in mice deficient in TRIF, Toll-like receptor 2 (TLR2), TLR3, TLR4, and TLR7 to determine the pathways through which IRF5 might promote arthritis. In vitro studies were performed to determine the role of IRF5 in interleukin-1 (IL-1) receptor and TLR signaling.
  
  
  RESULTS
  Arthritis severity was reduced in IRF5-deficient, TRIF-deficient, TLR3-deficient, and TLR7-deficient mice. The expression of multiple genes regulating neutrophil recruitment or function and bioactive IL-1β formation was reduced in the joints during active arthritis in IRF5-deficient mice. In vitro studies showed that TLR7 and the TRIF-dependent TLR3 pathway induce proinflammatory cytokine production in disease-relevant cell types in an IRF5-dependent manner.
  
  
  CONCLUSIONS
  Our findings indicate that IRF5 contributes to disease pathogenesis in inflammatory arthritis. This is likely due at least in part to the role of IRF5 in mediating proinflammatory cytokine production downstream of TLR7 and TLR3. Since TLR7 and TLR3 are both RNA-sensing TLRs, this suggests that endogenous RNA ligands present in the inflamed joint promote arthritis development. These findings may be relevant to human RA, since RNA capable of activating TLR7 and TLR3 is present in synovial fluid and TLR7 and TLR3 are up-regulated in the joints of RA patients.
authors: Boston University School of Medicine, Boston, Massachusetts, and Hôpital Saint-André, Centre Hospitalier Universitaire de Bordeaux and Université de Bordeaux, CNRS UMR 5164, Bordeaux, France.
authors: Pierre
authors: P
authors: Duffau
authors: Boston University School of Medicine, Boston, Massachusetts.
authors: Hanni
authors: H
authors: Menn-Josephy
authors: Northwestern University, Chicago, Illinois.
authors: Carla M
authors: CM
authors: Cuda
authors: Northwestern University, Chicago, Illinois.
authors: Salina
authors: S
authors: Dominguez
authors: Boston University School of Medicine, Boston, Massachusetts.
authors: Tamar R
authors: TR
authors: Aprahamian
authors: Boston University School of Medicine, Boston, Massachusetts.
authors: Amanda A
authors: AA
authors: Watkins
authors: Boston University School of Medicine, Boston, Massachusetts.
authors: Kei
authors: K
authors: Yasuda
authors: Boston University School of Medicine, Boston, Massachusetts.
authors: Paul
authors: P
authors: Monach
authors: Boston University School of Medicine, Boston, Massachusetts.
authors: Robert
authors: R
authors: Lafyatis
authors: Boston University School of Medicine, Boston, Massachusetts.
authors: Lisa M
authors: LM
authors: Rice
authors: Icahn School of Medicine at Mount Sinai, New York, New York.
authors: G
authors: G
authors: Kenneth Haines
authors: University of Massachusetts Medical School, Worcester.
authors: Ellen M
authors: EM
authors: Gravallese
authors: University of Massachusetts Medical School, Worcester.
authors: Rebecca
authors: R
authors: Baum
authors: Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, and Université de Bordeaux, CNRS UMR 5164, Bordeaux, France.
authors: Christophe
authors: C
authors: Richez
authors: Northwestern University, Chicago, Illinois.
authors: Harris
authors: H
authors: Perlman
authors: Boston University School of Medicine, Boston, Massachusetts.
authors: Ramon G
authors: RG
authors: Bonegio
authors: Boston University School of Medicine, Boston, Massachusetts.
authors: Ian R
authors: IR
authors: Rifkin
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics* / Q000276:immunology; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D066298:In Vitro Techniques; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology; D012720:Severity of Illness Index; D015398:Signal Transduction; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000235:genetics* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000235:genetics* / Q000276:immunology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D050835:Interferon Regulatory Factors; D053583:Interleukin-1beta; D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; C587672:IL1B protein, mouse; C498178:Irf5 protein, mouse; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C477038:Tlr7 protein, mouse