Background Chemokines are key pathophysiological mediators in the early phase of arthritis. Eotaxin-1 (Paquet and al., 2012) and its receptor, CCR-3 (CC Chemokine Receptor 3) (Haas and al., 2005), were previously shown to be highly expressed in the course of experimental arthritis. In human, CCR-3 positive monocytes are more abundant in the synovial fluid of arthritic patients than in healthy ones (Katschke and al., 2001). Moreover, RANTES, another chemokine with pathophysiological relevance to arthritis, is also a ligand of CCR-3, further suggesting that CCR-3 could be a potential therapeutic target for joint diseases.
Objectives The main obective of this project was to study consequences of CCR-3 inactivation by a pharmacological antagonist in collagen-induced arthritis.
Methods CIA was induced in 20 DBA/1J mice by intradermal injection of 100mg of bovine type II collagen in CFA at the basis of the tail, with a booster injection of 50mg by day 21. From day 15, mice were administered daily with antagonist of CCR-3 at a concentration of 10 mg/kg/day (i.p). Mice were regularly weighed and evaluated for the severity of arthritis with an arthritic score and by measuring hindpaw oedema by plethysmography. Mice were sacrificed at day 41, and histological analysis was performed on ankle joints after HES and safranin-O fast green staining. At that time, serum levels of IL-6 and IL-17F were measured by the multiplex technology.
Results The clinical parameters showed that mice treated with a specific antagonist of CCR-3 develop less severe arthritis (respective clinical score 3.89 ± 1.25 vs 8.57 ± 1.63). Histological analyzes indicated that antagonist reduced the intensity of inflammatory process and limits cartilage degradation in arthritic joints. Blood level of IL-6 and IL-17F cytokines were reduced in mice treated with antagonist of CCR-3 compared to untreated arthritic mice.
Conclusions Thus, our study shows that CCR-3 has an important role in arthritis development and designates it as a potential therapeutic target.
Haas C.S., Martinez R.J., Attia N., Kenneth H., Campbell P.L., Koch A.E., Chemokine receptor expression in rat adjuvant-induced arthritis. Arthritis and Rheumatism, 2005, 52, 3718–1730.
Katschke K.J., Jr., Rottman J.B., Ruth J.H., Qin S., Wu L., LaRosa G., Ponath P., Park C.C., Pope R.M., Koch A.E. Differential expression of chemokine receptors on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages in rheumatoid arthritis. Arthritis and Rheumatism, 2001, 44: 1022–1032.
Paquet J., Goebel, J-C, Delaunay C., Pinzano A., Grossin L., Cournil-Henrionnet C., Gillet P., Netter P., Jouzeau J-Y., Moulin D. Cytokines profiling by multiplex analysis in experimental arthritis: which pathophysiological relevance for articular versus systemic mediators? Arthritis Research and Therapy, 2012, 14: 60–75
Acknowledgement The authors thank fondation Arthritis for granting this study.
Disclosure of Interest None declared