| Abstract: | Objective Among many survival strategies, parasitic worms secrete molecules that modulate host immune responses. One such product, ES‐62, is protective against collagen‐induced arthritis (CIA), a model of rheumatoid arthritis (RA). Since interleukin‐17 (IL‐17) has been reported to play a pathogenic role in the development of RA, this study was undertaken to investigate whether targeting of IL‐17 may explain the protection against CIA afforded by ES‐62. Methods DBA/1 mice progressively display arthritis following immunization with type II collagen. The protective effects of ES‐62 were assessed by determination of cytokine levels, flow cytometric analysis of relevant cell populations, and in situ analysis of joint inflammation in mice with CIA. Results ES‐62 was found to down‐regulate IL‐17 responses in mice with CIA. First, it acted to inhibit priming and polarization of IL‐17 responses by targeting a complex IL‐17–producing network, involving signaling between dendritic cells and γ/δ or CD4+ T cells. In addition, ES‐62 directly targeted Th17 cells by down‐regulating myeloid differentiation factor 88 expression to suppress responses mediated by IL‐1 and Toll‐like receptor ligands. Moreover, ES‐62 modulated the migration of γ/δ T cells and this was reflected by direct suppression of CD44 up‐regulation and, as evidenced by in situ analysis, dramatically reduced levels of IL‐17–producing cells, including lymphocytes, infiltrating the joint. Finally, there was strong suppression of IL‐17 production by cells resident in the joint, such as osteoclasts within the bone areas. Conclusion Our findings indicate that ES‐62 treatment of mice with CIA leads to unique multisite manipulation of the initiation and effector phases of the IL‐17 inflammatory network. ES‐62 could be exploited in the development of novel therapeutics for RA. |
