Jones, Gareth Wyn, Greenhill, C. J., Williams, J. O., Nowell, Mari Ann, Williams, Anwen Sian  ORCID: https://orcid.org/0000-0001-6118-020X, Jenkins, B. J. and 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)
, pp. 1738-1742.
10.1136/annrheumdis-2013-203771
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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.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Medicine |
| Publisher: | BMJ Publishing Group |
| ISSN: | 0003-4967 |
| Date of First Compliant Deposit: | 30 March 2016 |
| Last Modified: | 05 Feb 2025 22:37 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/85516 |
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