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-) 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.