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

• Published in: International immunopharmacology 2020-07, Vol.84, p.106494, Article 106494
• Main Authors: Bakheet, Saleh A., Alrwashied, Bader S., Ansari, Mushtaq A., Nadeem, Ahmed, Attia, Sabry M., Assiri, Mohammed A., Alqahtani, Faleh, Ibrahim, Khalid E., Ahmad, Sheikh F.
• Format: Article
• Language: English
• Subjects: Acetamides - administration & dosage; Acetamides - pharmacology; Animal tissues; Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - pharmacology; Arthritis; Arthritis, Experimental - chemically induced; Arthritis, Experimental - drug therapy; Autoimmune diseases; Cartilage; CCR6 protein; CD25 antigen; CD4 antigen; CD45; CD45 antigen; Collagen; Collagen - pharmacology; Collagen-induced arthritis; CXCR3 antagonist; CXCR3 protein; Drug development; Flow cytometry; Foxp3 protein; Gene expression; GITR; Glucocorticoid-Induced TNFR-Related Protein - antagonists & inhibitors; Glucocorticoid-Induced TNFR-Related Protein - metabolism; Glucocorticoids; Health services; Inflammation; Inflammation Mediators - antagonists & inhibitors; Injections, Intraperitoneal; Interleukin 21; Interleukin 6; Interleukin 9; Interleukin-2 Receptor alpha Subunit - metabolism; Interleukins - metabolism; Joint diseases; Joints (anatomy); Knee; Leukocyte Common Antigens - metabolism; Lymphocyte Subsets - drug effects; Lymphocyte Subsets - metabolism; Male; Medical treatment; Mice; Mice, Inbred DBA; mRNA; NF-κB protein; Protein expression; Proteins; Pyrimidinones - administration & dosage; Pyrimidinones - pharmacology; Receptors, CXCR3 - antagonists & inhibitors; Rheumatoid arthritis; Spleen; Stat6 protein; T-Lymphocytes, Regulatory - metabolism; Tissue analysis
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2020.106494

•We investigated the effect of AMG487 on inflammatory mediators in CIA.•AMG487 suppresses inflammatory cytokine expression.•AMG487 treatment regulates IL-21 and STAT6 balance in CIA.•AMG487 treatment downregulated/decreased GITR-expressing T cell receptors in CIA.•Our data suggested that AMG487 may be an effective therapeutic agent for RA. 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.