CXC chemokine receptor 3 antagonist AMG487 shows potent anti-arthritic effects on collagen-induced arthritis by modifying B cell inflammatory profile.

Several studies have suggested that chemokine receptors are important mediators of inflammatory response in rheumatoid arthritis (RA). B cells are also known to play an important role in RA pathology. C-X-C chemokine receptor type 3 (CXCR3) is considered a potential therapeutic target in different inflammatory diseases; however, the mechanism remains unclear. Here, we evaluated the potentially protective effect of AMG487, a selective CXCR3 antagonist, in collagen-induced arthritis (CIA) mouse model. CIA mice were treated with AMG487 (5 mg/kg) every 48 h, from day 21 until day 41. We then investigated the effect of AMG487 on NF-κB p65-, NOS2-, MCP-1-, TNF-α-, IFN-γ, IL-4-, and IL-27-producing CD19+ B cells in the spleen through flow cytometry. We also evaluated the mRNA and protein expression levels of these molecules using RT-PCR and western blotting in the knee tissues. Our results revealed that AMG487-treated mice showed decreased NF-κB p65-, NOS2-, MCP-1-, and TNF-α-, and increased IL-4-, and IL-27-producing CD19+ B cells compared with the control mice. Additionally, AMG487 treatment significantly down regulated NF-κB p65, NOS2, TNF-α, and IFN-γ, and upregulated IL-4 and IL-27 mRNA and protein expression levels compared with the control. Thus, our study shows that AMG487 exerts its anti-arthritic effect by potently downregulating inflammatory B cell signaling. Based on our observations, we propose that AMG487 could serve as a potential novel therapeutic agent for inflammatory and autoimmune diseases, including RA.

CXCR3 antagonist AMG487 inhibits glucocorticoid-induced tumor necrosis factor-receptor-related protein and inflammatory mediators in CD45 expressing cells in collagen-induced arthritis mouse model.

Rheumatoid arthritis (RA) is an autoimmune disease classified by uncontrolled joint inflammation leading to the destruction of both cartilage and joints. Despite progress made in RA treatment in the past decade, new drugs with high efficacy and fewer long-term adverse effects are still needed; thus, safe anti-inflammatory therapies for RA are urgently needed. Previous results demonstrated that the CXCR3 antagonist is an extremely attractive therapeutic target for the treatment of several autoimmune diseases, suggesting that it might have an inhibitory effect on RA. In this study, we investigated the effect of AMG487, a selective CXCR3 antagonist, on collagen-induced arthritis (CIA) in mice and evaluated its potential therapeutic mechanism.Following induction of CIA, mice were treated with AMG487 (5 mg/kg, intraperitoneally), to investigate their protective effects against CIA. CD4, CD25, CCR6, IL-9, NF-κB, IL-6, IL-17A, IL-21, STAT6 and Foxp3 expressing GITR+ and CD45+ cells were measured in the spleen using flow cytometry to assess anti-inflammatory effects of AMG487. The mRNA and protein expression of GITR, CCR6, IL-9, and IL-21 were measured using quantitative real-time PCR and western blot analysis in knee tissue. AMG487 significantly alleviated joint inflammation by decreasing GITR+CD25+, GITR+CD45+, GITR+IL-9+, GITR+NF-κB+ CD45+CD4+, CD45+CCR6+, CD45+IL-6+ cells, CD45+IL-17A+, and CD45+IL-21+, and increasing GITR+Foxp3+ and GITR+STAT6+ cells. There was a significant decrease in mRNA and protein expression of GITR, CD4, CCR6, IL-6, IL-9, and IL-21 in knee tissue of CIA mice. This study demonstrates that AMG487 has a potential therapeutic effect on RA and could explore novel anti-inflammatory therapies for its treatment.