Abstract
Objective
CC chemokines and their receptors play a fundamental role in trafficking and activation of leukocytes at sites of inflammation, contributing to joint damage in rheumatoid arthritis. Met‐RANTES, an amino‐terminal–modified methionylated form of RANTES (CCL5), antagonizes the binding of the chemokines RANTES and macrophage inflammatory protein 1α (MIP‐1α; CCL3) to their receptors CCR1 and CCR5, respectively. The aim of this study was to investigate whether Met‐RANTES could ameliorate adjuvant‐induced arthritis (AIA) in the rat.
Methods
Using immunohistochemistry, enzyme‐linked immunosorbent assay, real‐time reverse transcription–polymerase chain reaction, Western blot analysis, adoptive transfer, and chemotaxis, we defined joint inflammation, bony destruction, neutrophil and macrophage migration, Met‐RANTES binding affinity to rat receptors, proinflammatory cytokine and bone marker levels, CCR1 and CCR5 expression and activation, and macrophage homing into joints with AIA.
Results
Administration of Met‐RANTES as a preventative reduced the severity of joint inflammation. Administration of Met‐RANTES to ankles with AIA showed decreases in inflammation, radiographic soft tissue swelling, and bone erosion. Met‐RANTES significantly reduced the number of neutrophils and macrophages at the peak of arthritis compared with saline‐injected controls. Competitive chemotaxis in peripheral blood mononuclear cells demonstrated that Met‐RANTES inhibited MIP‐1α and MIP‐1β at 50% inhibition concentrations of 5 n__M__ and 2 n__M__, respectively. Furthermore, levels of tumor necrosis factor α, interleukin‐1β, macrophage colony‐stimulating factor, and RANKL were decreased in joints with AIA in the Met‐RANTES group compared with the control group. Interestingly, the expression and activation of CCR1 and CCR5 in the joint were down‐regulated in the Met‐RANTES group compared with the control group. Functionally, Met‐RANTES administration decreased adoptively transferred peritoneal macrophage homing into the joint.
Conclusion
The data suggest that the targeting of Th1‐associated chemokine receptors reduce joint inflammation, bone destruction, and cell recruitment into joints with AIA.