Session Type: Abstract Submissions (ACR)
Background/Purpose: T helper-17 (Th17) cells are important mediators of inflammatory diseases, and are the main pathogenic cell type in many animal models of autoimmunity. Recent studies highlight a surprising role for T-cell derived granulocyte-macrophage colony stimulating factor (GM-CSF) in the pathogenicity of Th17 cells. We examined the mechanism by which interleukin 17 (IL-17) and GM-CSF contribute to cartilage- and bone damage of synovial joints during experimental arthritis, and provide a rationale for combination therapy in auto-inflammatory conditions.
Methods: Collagen-induced arthritis was elicited in DBA/1J mice. Neutralizing antibodies to IL-17 and/or GM-CSF were administered after onset of disease for 14 days. Arthritis progression was followed by macroscopic scoring of the paws (maximum score of 12 per mouse). In addition, the effect of local over-expression of IL-17 and/or GM-CSF was studied by adenoviral transfection in naïve knee joints. Knee- and ankle joints, synovial tissue and serum from both experiments were analyzed in detail for the presence of cytokines, chemokines, and matrix metalloproteinases (MMPs). Cartilage- and bone damage was determined by histological analysis.
Results: Combined therapeutic treatment of mice during arthritis ameliorated disease progression. Macroscopic joint inflammation was significantly reduced, from a total score of 5.6 ± 0.4 for mice treated with isotype control antibodies to 2 ± 0.6 for mice treated with combination therapy. Treatment with anti-IL-17 or anti-GM-CSF alone resulted in scores of 3.4 ± 0.5 and 3.5 ± 0.4, respectively. Anti-IL-17 specifically reduced the transcription of IL-23 in the synovium, whereas anti-GM-CSF inhibited production of MMPs, Receptor Activator of NF-κB Ligand (RANKL), and monocyte-chemotactic protein-1 (MCP-1, CCL2). Serum IL-6 was reduced in all treatment groups compared to control mice. To provide further insight in local additive or synergistic effects of IL-17 and GM-CSF, overexpression of IL-17, GM-CSF or the combination was achieved with adenoviral vectors. Inflammatory infiltrate and cartilage- and bone damage developed in all groups from day 1 after adenoviral transfer, with the most severe effect observed in the combination group. On day 7, partial destruction of joint architecture was apparent in knee joints after combined overexpression of IL-17 and GM-CSF. Overexpression of IL-17 alone caused a specific increase in synovial IL-6 production. Overexpression of GM-CSF alone induced IL-1β, S100A8 and MMP13 in synoviocytes. A strong synergistic effect of combined overexpression was seen on the production of the endogenous damage-associated molecular patterns (DAMP) ligand S100A8, the osteoclast activator RANKL and the Th17 differentiation factor IL-23.
Conclusion: We show that IL-17 and GM-CSF cause joint damage through synergistic effects on inflammatory mediators in synovial joints. In view of the moderate success of therapeutic IL-17 or GM-CSF blockade in rheumatoid arthritis, combined inhibition of IL-17 and GM-CSF might be an option for patients that do not fully respond to inhibition of the separate cytokines.
A. E. M. Van Nieuwenhuijze,
F. A. J. Van de Loo,
M. B. Bennink,
M. M. Helsen,
L. Van den Bersselaar,
I. P. Wicks,
W. B. Van den Berg,
M. I. Koenders,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/synergism-between-granulocyte-macrophage-colony-stimulating-factor-and-interleukin-17-causes-joint-damage-via-the-production-of-interleukin-23-receptor-activator-of-nf-%ce%bab-ligand-and-s100a8/