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

Gareth Jones, Claire J Greenhill, Julie O Williams, Mari A Nowell, Anwen S Williams, Brendan John Jenkins, Simon A Jones

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

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 languageEnglish
Pages (from-to)1738 - 1742
Number of pages5
JournalAnnals of the Rheumatic Diseases
Volume72
Issue number10
DOIs
Publication statusPublished - 2013

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