Exacerbated inflammatory arthritis in response to hyperactive gp130 signalling is independent of IL-17A

Gareth Wyn Jones, C. J. Greenhill, J. O. Williams, Mari Ann Nowell, Anwen Sian Williams, B. J. Jenkins, S. A. Jones

Research output: Contribution to journalArticle (Academic Journal)

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-gamma) 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.
Original languageUndefined/Unknown
Pages (from-to)1738-1742
Number of pages5
JournalAnnals of the Rheumatic Diseases
Volume72
Issue number10
Publication statusPublished - 1 Oct 2013

Cite this

Jones, G. W., Greenhill, C. J., Williams, J. O., Nowell, M. A., Williams, A. S., Jenkins, B. J., & Jones, S. A. (2013). Exacerbated inflammatory arthritis in response to hyperactive gp130 signalling is independent of IL-17A. Annals of the Rheumatic Diseases, 72(10), 1738-1742. http://orca.cf.ac.uk/85516/