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

Objective Interleukin (IL)-17A producing CD4 T-cells (T H -17 cells) are implicated in rheumatoid arthritis (RA). IL-6/STAT3 signalling drives T H -17 cell differentiation, and hyperactive gp130/STAT3 signalling in the gp130 F/F mouse promotes exacerbated pathology. Conversely, STAT1-activating cytokines (eg, IL-27, IFN-γ) inhibit T H -17 commitment. Here, we evaluate the impact of STAT1 ablation on T H -17 cells during experimental arthritis and relate this to IL-17A-associated pathology. Methods Antigen-induced arthritis (AIA) was established in wild type (WT), gp130 F/F mice displaying hyperactive gp130-mediated STAT signalling and the compound mutants gp130 F/F :Stat1 −/− and gp130 F/F :Il17a −/− mice. Joint pathology and associated peripheral T H -17 responses were compared. Results Augmented gp130/STAT3 signalling enhanced T H -17 commitment in vitro and exacerbated joint pathology. Ablation of STAT1 in gp130 F/F mice ( gp130 F/F :Stat1 −/− ) promoted the hyperexpansion of T H -17 cells in vitro and in vivo during AIA. Despite this heightened peripheral T H -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 gp130 F/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.