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

• Published in: Immunology letters 2020-09, Vol.225, p.74-81
• Main Authors: Bakheet, Saleh A., Alrwashied, Bader S., Ansari, Mushtaq A., Nadeem, Ahmed, Attia, Sabry M., Alanazi, Mohammed M., Aldossari, Abdullah A., Assiri, Mohammed A., Mahmood, Hafiz M., Al-Mazroua, Haneen A., Ahmad, Sheikh F.
• Format: Article
• Language: English
• Subjects: Autoimmune disease; CD19+B cells; Collagen-induced arthritis; CXCR3 antagonist; DBA/1J mice
• ISSN: 0165-2478; 1879-0542
• DOI: 10.1016/j.imlet.2020.06.014

[Display omitted] •We investigated the effect of AMG487 on the key mediators of RA.•AMG487 treatment downregulated NF-κB signaling in collagen-induced arthritis mice.•AMG487 treatment significantly decreases proinflammatory cytokines in CIA mice.•AMG487-treated mice show upregulation of anti-inflammatory cytokines.•AMG487 exhibits anti-arthritic activity and is a viable therapeutic option for RA. 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.