The role of Cas-L/NEDD9 as a regulator of collagen-induced arthritis in a murine model

Abstract Cas-L/NEDD9 is a cytoplasmic docking protein downstream of β1 integrin-mediated signaling pathway and is essential for cellular migration and β1 integrin-mediated costimulation of T cells. We previously found that increased number of Cas-L positive leukocytes migrated into the inflamed joints of HTLV-I tax transgenic mice which spontaneously develop polyarthritis, suggesting a role of Cas-L in rheumatoid arthritis (RA) pathophysiology. Our current study expanded these findings on the role of Cas-L/NEDD9 in the development of RA by analyzing the pathophysiological changes in a Nedd9 −/− mouse collagen-induced arthritis (CIA) model. Nedd9 −/− mice exhibited a decrease in arthritis severity as compared to Nedd9 +/+ mice. In addition, as being conducted bone marrow transplantation experiments with a CIA model, Nedd9 −/− → Nedd9 +/+ transplant showed a decrease in the incidence and severity score of arthritis, compared to those of Nedd9 +/+ → Nedd9 −/− transplant. For analysis of serum levels of various cytokines, IL-1β, IL-6, IL-17, TNF-α, IFN-γ and anti-collagen antibody were decreased, while IL-4 and IL-10 levels were increased, in Nedd9 −/− mice as compared to those in Nedd9 +/+ mice. Furthermore, collagen-mediated cellular responses of lymphocytes isolated from spleen or affected lymph nodes of Nedd9 −/− mice were reduced. Our results strongly suggest that Cas-L/NEDD9 plays a pivotal role in the pathophysiology of CIA, and that Cas-L/NEDD9 may be a potential molecular target for the treatment of RA.