Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Anti-CXCL5 Therapy Ameliorates IL-17 Induced Arthritis.
Pickens4, Sarah R., Volin1, Michael V., Mandelin2, Arthur M., Shahrara3, Shiva
Since CXCL1 and 5 are important downstream targets of IL-17, experiments were performed to determine whether CXCL1 and/or CXCL5 play a role in arthritis mediated by local IL-17 expression in mice ankle joints.
Mice were treated intraperitoneally with IgG, anti-CXCL1, anti-CXCL5 or both anti-CXCL1 and anti-CXCL5 antibodies on days -4, -2, 0, 3, 5, 7 and 9 post-adenovirus (Ad) injection and arthritis was induced by injecting Ad-IL-17 intra-articularly on day 0. The disease activity was determined by measuring ankle circumference and performing histological studies. Since the expression of proinflammatory mediators is characteristic of joint inflammation, the effect of therapy on joint TNF-a, IL-6, IL-1b, CCL2, CCL3, CCL5, CCL20 and CXCL2 was examined by ELISA. Additionally, neutrophil infiltration was measured by staining ankles harvested from different treatment groups with an antibody for neutrophil marker GR1.
The disease activity determined by articular index score and ankle circumference was significantly lower in mice receiving anti-CXCL1 on days 3 and 5 compared to the control group. However, as the arthritis progressed there was no difference noted at later time points (days 7 and 9). In contrast, mice receiving anti-CXCL5 demonstrated significantly reduced clinical signs of arthritis compared to the mice treated with IgG control. The combination of anti-CXCL1 and 5 did not ameliorate IL-17 induced joint inflammation beyond the effect observed using anti-CXCL5 alone. Hence, the clinical efficacy is due to neutralization of joint CXCL5. Consistently, while inflammation, synovial lining thickening, and bone erosion were markedly reduced in the anti-CXCL5 and anti-CXCL1+5 treatment groups, mice receiving anti-CXCL1 antibody had similar clinical scores compared to the control group. The effect of therapy on joint TNF-a, IL-6, IL-1b, CCL2, CCL3, CCL5, CCL20 and CXCL2 was examined. Our results demonstrate that mice receiving anti-CXCL5 or anti-CXCL1 and 5 had significantly lower levels of joint TNF-a and RANTES compared to the control group. Reduction in joint TNF-a levels in the anti-CXCL5 and combination therapy may be due to the fact that IL-17 induced joint pathology is abrogated in TNF-a-/- mice indicating that in this model TNF-a is required, and therefore suppression in the inflammatory response modulates levels of this cytokine. Additionally, since both TNF-a and IL-17 synergize in inducing the expression of CXCL5 from RA ST fibroblasts, neutralization of CXCL5 may negatively regulate joint TNF-a concentration. GR1 staining demonstrated that the mice receiving anti-CXCL5 or anti-CXCL1 and 5 had significantly reduced neutrophil migration compared to anti-CXCL1 and IgG therapy.
Our results suggest that expression of CXCR2 ligand, CXCL5, and not CXCL1 plays an important role in IL-17 mediated arthritis potentially through modulating TNF-a levels.
To cite this abstract, please use the following information:
Pickens, Sarah R., Volin, Michael V., Mandelin, Arthur M., Shahrara, Shiva; Anti-CXCL5 Therapy Ameliorates IL-17 Induced Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :270