Alamandine, a new member of the renin-angiotensin system (RAS), attenuates collagen-induced arthritis in mice via inhibiting cytokine secretion in synovial fibroblasts
Alamandine, a new member of the renin-angiotensin system (RAS), attenuates collagen-induced arthritis in mice via inhibiting cytokine secretion in synovial fibroblasts
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DOI：
10.1016/j.peptides.2022.170816
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发表时间：
2022-05-26
期刊：
影响因子：
3
通讯作者：
Wang, Fang
中科院分区：
文献类型：
--
作者：
Ding, Wei;Miao, Zhengyue;Wang, Fang
Alamandine是一种新的肾素-血管紧张素系统（RAS）组分，也是一种重要的生物活性肽。它主要在心血管背景下进行研究。然而，其在类风湿性关节炎（RA）中的作用仍然未知。在这里，我们阐述了其对RA滑膜成纤维细胞产生炎性细胞因子和胶原诱导的关节炎（CIA）小鼠的病理变化的影响。Alamandine（0.1，1和10 μ g/ml）不影响滑膜成纤维细胞的存活，但降低了TNF-α（10 ng/ml）刺激的细胞在体外的迁移和促炎细胞因子的表达。此外，Alamandine选择性降低RA FLS中TNF-α刺激诱导的磷酸化JNK表达。通过初次注射牛II型胶原（CII）和完全弗氏佐剂的乳液（第0天）和加强注射在不完全弗氏佐剂中的CII（第21天）诱导DBA/1 J小鼠关节炎。然后从第21-42天腹膜内给予小鼠在盐水中的alamandine（50 μ g/kg/天）。组织学和多重免疫球蛋白试验表明，阿拉曼定治疗抑制了关节炎的发展，减轻了关节损伤。这种作用伴随着局部关节中炎性细胞因子（IL-6、IL-23、IFN-γ）mRNA表达的降低，来自Alamandine给药的CIA小鼠的血清中TNF-α、IL-6、IL-17水平的降低和IL-10水平的增加。总之，阿拉曼丁通过MAPK信号通路抑制RA滑膜成纤维细胞中炎症细胞因子的表达，从而减轻关节炎的发展，这表明阿拉曼丁对RA具有潜在的治疗作用。
Alamandine is a novel component of the renin-angiotensin system (RAS) as well as an important biologically active peptide. It has predominantly been studied in cardiovascular context. However, its role in rheumatoid arthritis (RA) remains unknown. Here we illustrated its effects on inflammatory cytokines production by synovial fibroblasts from RA and pathological changes in collagen-induced arthritis (CIA) mice. Alamandine (0.1, 1 and 10 mu g/ml) did not affect the survival of the synovial fibroblasts, but decreased the migration and proinflammatory cytokines expression in TNF-alpha (10 ng/ml) stimulated cells in vitro. Additionally, alamandine selectively decreased phosphorylated-JNK expression induced by TNF-a stimulation in RA FLS. DBA/1 J mice were induced arthritis by a primary injection with an emulsion of bovine type II collagen (CII) and complete Freund's adjuvant (day 0) and a booster injection of CII in incomplete Freund's adjuvant (day 21). Mice were then given alamandine intraperitoneally in saline (50 mu g/kg/day) from days 21-42. Histology and multiplex immunobead assay showed that alamandine treatment inhibited the development of arthritis and reduced the joint damage. This effect was accompanied by the reduced inflammatory cytokines (IL-6, IL-23, IFN-gamma) mRNA expression in local joints, the decreased TNF-alpha, IL-6, IL-17 and the increased IL-10 levels in the serum from alamandine administrated CIA mice. In conclusion, alamandine attenuates the development of arthritis by suppressing inflammatory cytokines expression in RA synovial fibroblasts via MAPK signaling pathway, suggesting a potential therapeutic role for RA.