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Exacerbated inflammatory arthritis in response to hyperactive gp130 signalling is independent of IL-17A
  1. G W Jones1,2,
  2. C J Greenhill1,
  3. J O Williams1,
  4. M A Nowell1,
  5. A S Williams1,
  6. B J Jenkins2,
  7. S A Jones1
  1. 1Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, Wales, UK
  2. 2Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia
  1. Correspondence to Professor S A Jones, Cardiff Institute of Infection and Immunity, The School of Medicine, Cardiff University, The Tenovus Building, Heath Campus, Cardiff, CF14 4XN, UK; JonesSA{at}cf.ac.uk

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.

  • Cytokines
  • Inflammation
  • Rheumatoid Arthritis
  • T Cells

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/

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