title: Exacerbated inflammatory arthritis in response to hyperactive gp130 signalling is independent of IL-17A.
abstract: OBJECTIVE
  Interleukin (IL)-17A producing CD4 T-cells (TH-17 cells) are implicated in rheumatoid arthritis (RA). IL-6/STAT3 signalling drives TH-17 cell differentiation, and hyperactive gp130/STAT3 signalling in the gp130F/F mouse promotes exacerbated pathology. Conversely, STAT1-activating cytokines (eg, IL-27, IFN-γ) inhibit TH-17 commitment. Here, we evaluate the impact of STAT1 ablation on TH-17 cells during experimental arthritis and relate this to IL-17A-associated pathology.
  
  
  METHODS
  Antigen-induced arthritis (AIA) was established in wild type (WT), gp130F/F mice displaying hyperactive gp130-mediated STAT signalling and the compound mutants gp130F/F:Stat1-/- and gp130F/F:Il17a-/- mice. Joint pathology and associated peripheral TH-17 responses were compared.
  
  
  RESULTS
  Augmented gp130/STAT3 signalling enhanced TH-17 commitment in vitro and exacerbated joint pathology. Ablation of STAT1 in gp130F/F mice (gp130F/F:Stat1-/-) promoted the hyperexpansion of TH-17 cells in vitro and in vivo during AIA. Despite this heightened peripheral TH-17 cell response, disease severity and the number of joint-infiltrating T-cells were comparable with that of WT mice. Thus, gp130-mediated STAT1 activity within the inflamed synovium controls T-cell trafficking and retention. To determine the contribution of IL-17A, we generated gp130F/F:IL-17a-/- mice. Here, loss of IL-17A had no impact on arthritis severity.
  
  
  CONCLUSIONS
  Exacerbated gp130/STAT-driven disease in AIA is associated with an increase in joint infiltrating T-cells but synovial pathology is IL-17A independent.
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, Wales, UK.
authors.forename: G W
authors.initials: GW
authors.lastname: Jones
authors.forename: C J
authors.initials: CJ
authors.lastname: Greenhill
authors.forename: J O
authors.initials: JO
authors.lastname: Williams
authors.forename: M A
authors.initials: MA
authors.lastname: Nowell
authors.forename: A S
authors.initials: AS
authors.lastname: Williams
authors.forename: B J
authors.initials: BJ
authors.lastname: Jenkins
authors.forename: S A
authors.initials: SA
authors.lastname: Jones
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000276:immunology*; D020381:Interleukin-17 / Q000172:deficiency / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology; D058504:Th17 Cells / Q000473:pathology
chemical_list: C494200:Il6st protein, mouse; D020381:Interleukin-17; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D050822:Cytokine Receptor gp130
keywords: Cytokines; Inflammation; Rheumatoid Arthritis; T Cells
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