Research Institute for Medical Sciences, Chungnam National University School of Medicine, 266 Munhwaro, Daejeon, Republic of Korea.
Division of Rheumatology, Department of Internal Medicine, Chungnam National University Hospital, 282 Munhwaro, Daejeon, 35015, Republic of Korea.
Arthritis Res Ther. 2020 May 15;22(1):116. doi: 10.1186/s13075-020-02204-0.
Reactive oxygen species (ROS) regulate the migration and invasion of fibroblast-like synoviocytes (FLS), which are key effector cells in rheumatoid arthritis (RA) pathogenesis. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) induces ROS generation and, consequently, enhances cell migration. Despite the important interrelationship between RA, FLS, and ROS, the effect of NOX4 on RA pathogenesis remains unclear.
FLS isolated from RA (n = 5) and osteoarthritis (OA, n = 5) patients were stimulated with recombinant interleukin 17 (IL-17; 10 ng/ml) and tumor necrosis factor alpha (TNF-α; 10 ng/ml) for 1 h. Cell migration, invasion, adhesion molecule expression, vascular endothelial growth factor (VEGF) secretion, and ROS expression were examined. The mRNA and protein levels of NOX4 were analyzed by RT-qPCR and western blotting, respectively. The NOX4 inhibitor GLX351322 and NOX4 siRNA were used to inhibit NOX4 to probe the effect of NOX4 on these cellular processes.
Migration of RA FLS was increased 2.48-fold after stimulation with IL-17 and TNF-α, while no difference was observed for OA FLS. ROS expression increased in parallel with invasiveness of FLS following cytokine stimulation. When the expression of NOX was examined, NOX4 was significantly increased by 9.73-fold in RA FLS compared to unstimulated FLS. Following NOX4 inhibition, cytokine-induced vascular cell adhesion molecule 1 (VCAM1), VEGF, and migration and invasion capacity of RA FLS were markedly decreased to unstimulated levels.
NOX4 is a key contributor to cytokine-enhanced migration and invasion via modulation of ROS, VCAM1, and VEGF in RA FLS.
活性氧（ROS）调节成纤维样滑膜细胞（FLS）的迁移和侵袭，FLS 是类风湿关节炎（RA）发病机制中的关键效应细胞。烟酰胺腺嘌呤二核苷酸磷酸氧化酶 4（NOX4）诱导 ROS 的产生，从而增强细胞迁移。尽管 RA、FLS 和 ROS 之间存在重要的相互关系，但 NOX4 对 RA 发病机制的影响尚不清楚。
从 RA（n=5）和骨关节炎（OA，n=5）患者中分离出 FLS，用重组白细胞介素 17（IL-17；10ng/ml）和肿瘤坏死因子-α（TNF-α；10ng/ml）刺激 1h。检测细胞迁移、侵袭、黏附分子表达、血管内皮生长因子（VEGF）分泌和 ROS 表达。通过 RT-qPCR 和 Western blot 分别分析 NOX4 的 mRNA 和蛋白水平。使用 NOX4 抑制剂 GLX351322 和 NOX4 siRNA 抑制 NOX4，以探讨 NOX4 对这些细胞过程的影响。
IL-17 和 TNF-α刺激后，RA FLS 的迁移增加了 2.48 倍，而 OA FLS 则没有差异。细胞因子刺激后，FLS 的 ROS 表达与侵袭性平行增加。当检查 NOX 的表达时，与未刺激的 FLS 相比，NOX4 在 RA FLS 中的表达增加了 9.73 倍。抑制 NOX4 后，细胞因子诱导的血管细胞黏附分子 1（VCAM1）、VEGF 以及 RA FLS 的迁移和侵袭能力明显降低至未刺激水平。
NOX4 通过调节 RA FLS 中的 ROS、VCAM1 和 VEGF，是细胞因子增强迁移和侵袭的关键因素。
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