Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Int Immunopharmacol. 2023 May;118:110099. doi: 10.1016/j.intimp.2023.110099. Epub 2023 Apr 3.
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by uncontrolled synovial proliferation, pannus formation, cartilage injury, and bone destruction. We used the CXCR3-specific antagonist NBI-74330 to block T-cell-mediated signaling in a DBA/1J mouse model of collagen-induced arthritis (CIA). After CIA induction, DBA/1J mice were treated with NBI-74330 (100 mg/kg) daily from day 21 until day 34 and evaluated for arthritic score and histopathological changes. Furthermore, using flow cytometry, we investigated the effects of NBI-74330 on Th1 (IFN-γ, TNF-α, T-bet, STAT4, Notch-3, and RANKL), Th17 (IL-21, IL-17A, STAT3, and RORγt), and Th22 (IL-22) cells in splenic CD4 and CXCR3T-cells. We also used RT-PCR to assess the effect of mRNA levels of IFN-γ, TNF-α, T-bet, RANKL, IL-17A, RORγt, and IL-22 in knee tissues. The IFN-γ, TNF-α, and IL-17A serum protein levels were measured using ELISA. Compared to vehicle-treated CIA mice, the severity of arthritic scores and histological severity of inflammation decreased significantly in NBI-74330-treated CIA mice. Moreover, compared to vehicle-treated CIA mice, the percentages of CD4IFN-γ, CD4TNF-α, CD4T-bet, CD4STAT4, CD4Notch-3, CXCR3IFN-γ, CXCR3TNF-α, CXCR3T-bet, CXCR3STAT4, CXCR3Notch-3, CD4RANKL, CD4IL-21, CD4IL-17A, CD4STAT3, CD4RORγt, and CD4IL-22 cells decreased in NBI-74330-treated CIA mice. Furthermore, NBI-74330-treatment downregulated IFN-γ, TNF-α, T-bet, RANKL, STAT3, IL-17A, RORγt, and IL-22 mRNA levels. Serum IFN-γ, TNF-α, and IL-17A levels were significantly lower in NBI-74330-treated CIA mice than in vehicle-treated CIA mice. This study demonstrates the antiarthritic effects of NBI-74330 in CIA mice. Therefore, these data suggest that NBI-74330 could be considered a potential RA treatment.
类风湿关节炎（RA）是一种慢性炎症性疾病，其特征为滑膜不受控制的增生、血管翳形成、软骨损伤和骨破坏。我们使用 CXCR3 特异性拮抗剂 NBI-74330 阻断 DBA/1J 小鼠胶原诱导性关节炎（CIA）模型中的 T 细胞介导的信号传导。在 CIA 诱导后，DBA/1J 小鼠从第 21 天到第 34 天每天接受 NBI-74330（100mg/kg）治疗，并评估关节炎评分和组织病理学变化。此外，我们使用流式细胞术研究了 NBI-74330 对脾 CD4 和 CXCR3T 细胞中 Th1（IFN-γ、TNF-α、T-bet、STAT4、Notch-3 和 RANKL）、Th17（IL-21、IL-17A、STAT3 和 RORγt）和 Th22（IL-22）细胞的影响。我们还使用 RT-PCR 评估了 NBI-74330 对膝关节组织中 IFN-γ、TNF-α、T-bet、RANKL、IL-17A、RORγt 和 IL-22 mRNA 水平的影响。使用 ELISA 测量 IFN-γ、TNF-α 和 IL-17A 的血清蛋白水平。与 vehicle 处理的 CIA 小鼠相比，NBI-74330 处理的 CIA 小鼠的关节炎评分严重程度和炎症组织学严重程度显著降低。此外，与 vehicle 处理的 CIA 小鼠相比，NBI-74330 处理的 CIA 小鼠中 CD4IFN-γ、CD4TNF-α、CD4T-bet、CD4STAT4、CD4Notch-3、CXCR3IFN-γ、CXCR3TNF-α、CXCR3T-bet、CXCR3STAT4、CXCR3Notch-3、CD4RANKL、CD4IL-21、CD4IL-17A、CD4STAT3、CD4RORγt 和 CD4IL-22 细胞的百分比降低。此外，NBI-74330 治疗下调了 IFN-γ、TNF-α、T-bet、RANKL、STAT3、IL-17A、RORγt 和 IL-22 mRNA 水平。与 vehicle 处理的 CIA 小鼠相比，NBI-74330 处理的 CIA 小鼠的血清 IFN-γ、TNF-α 和 IL-17A 水平显著降低。这项研究表明 NBI-74330 对 CIA 小鼠具有抗关节炎作用。因此，这些数据表明 NBI-74330 可被视为一种潜在的 RA 治疗方法。
