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

• Published in: Annals of the rheumatic diseases Vol. 72; no. 10; pp. 1738 - 1742
• Main Authors: Jones, G W, Greenhill, C J, Williams, J O, Nowell, M A, Williams, A S, Jenkins, B J, Jones, S A
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and European League Against Rheumatism 01.10.2013; BMJ Publishing Group LTD; BMJ Publishing Group
• Series: Concise report
• Subjects: Animals; Antigens; Arthritis; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; Basic and Translational Research; Cell culture; Cells, Cultured; Chemokines; Cytokine Receptor gp130 - immunology; Cytokines; Disease; Histopathology; Inflammation; Interleukin-17 - deficiency; Interleukin-17 - immunology; Ligands; Mice; Mice, Knockout; Pathology; Rheumatoid Arthritis; Signal Transduction - immunology; STAT1 Transcription Factor - deficiency; STAT1 Transcription Factor - immunology; Synovial Membrane - immunology; T Cells; Th17 Cells - pathology; Tumor necrosis factor-TNF; Inflammation; T Cells; Cytokines; Rheumatoid Arthritis
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2013-203771

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.