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

Jones, Gareth Wyn, Greenhill, C. J., Williams, J. O., Nowell, Mari Ann, Williams, Anwen Sian, 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: Medicine
Publisher: BMJ Publishing Group
ISSN: 0003-4967
Date of First Compliant Deposit: 30 March 2016
Last Modified: 24 Aug 2018 22:26
URI: http://orca.cf.ac.uk/id/eprint/85516

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