siRNA-mediated c-Rel knockdown ameliorates collagen-induced arthritis in mice

Previous studies have shown that inflammatory mediators involved in the development of rheumatoid arthritis (RA) are regulated by the Rel/nuclear factor-κB (Rel/NF-κB) transcription factor family. c-Rel, a member of the Rel/NF-κB family that is preferentially expressed by immune cells, is a risk factor for several inflammatory diseases including RA. In the current study, we investigated whether targeting c-Rel can be used to treat collagen-induced arthritis, an animal model for RA. c-Rel specific siRNA (siRel) delivered by nanoparticles was used to knockdown the expression of c-Rel. Our results showed that siRel treatment significantly ameliorated collagen-induced arthritis. Further study revealed that c-Rel expression in the dendritic cells and macrophages from mice treated with siRel was significantly down-regulated. Consistent with the phenotypical result, the expression of inflammatory cytokines TNF-α, IL-1β, IL-6, IL-12 and IL-23 by peritoneal macrophages and splenocytes were significantly decreased. In addition, attenuated systemic and collagen-specific Th1 and Th17 immune responses were observed. Furthermore, we found that the expression of inflammatory cytokines was significantly down-regulated and the infiltration of CD3+ T cells and F4/80+ macrophages was markedly reduced in hind paws of mice treated with siRel. Collectively, our study provides strong evidence that siRNA-mediated c-Rel knockdown can suppress the development of collagen-induced arthritis in mice. Therefore, blocking c-Rel may represent an attracting strategy for the treatment of human rheumatoid arthritis.