The role of high-mobility group box protein 1 in collagen antibody-induced arthritis is dependent on vascular endothelial growth factor
The role of high-mobility group box protein 1 in collagen antibody-induced arthritis is dependent on vascular endothelial growth factor
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DOI：
10.1111/cei.12758
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发表时间：
2016-04-01
影响因子：
4.6
通讯作者：
Ferraccioli, G.
中科院分区：
文献类型：
--
作者：
Biscetti, F.;Flex, A.;Ferraccioli, G.
高迁移率族蛋白 1 (HMGB1) 与血管生成和类风湿性关节炎 (RA) 相关。本研究的目的是更清楚地定义 HMGB1 在关节炎免疫模型滑膜血管生成和发病机制中的作用。 BALB/c 小鼠注射单克隆抗胶原抗体混合物，然后注射脂多糖以诱导关节炎。 HMGB1 和血管内皮生长因子 (VEGF) 在存在更多炎症和新血管生成的滑膜区域过度表达。选择性阻断 HMGB1 或 VEGF 或者导致关节炎指数评估的关节炎严重程度降低。此外，外源性 HMGB1 给药会导致关节炎恶化，这与 VEGF 上调和滑膜血管生成增加有关。选择性抑制 VEGF 也不会导致接受外源 HMGB1 的小鼠诱发关节炎。对外周血和滑液进行的细胞因子酶联免疫吸附测定 (ELISA) 分析表明，在 HMGB1 和 VEGF 途径被阻断的小鼠中，白细胞介素 (IL)-1、IL-6 和肿瘤坏死因子 (TNF) 显着减少。有趣的是，选择性阻断 HMGB1 和 VEGF 导致外周 IL-17A 浓度增加。 HMGB1 介导的关节炎的发展和滑膜血管生成可以通过抑制 VEGF 活性来阻断。当 HMGB1 被抑制时，促炎和促血管生成细胞因子 IL-17A 增加，但在这种关节炎模型中滑膜血管生成仍然减少。总而言之，这些发现为这种核蛋白在类 RA 模型中关节炎发病机制中的作用提供了新的线索。
High-mobility group box 1 (HMGB1) has been implicated in angiogenesis and rheumatoid arthritis (RA). The aim of this study was to define more clearly the role of HMGB1 in the synovial angiogenesis and pathogenesis of an immune model of arthritis. BALB/c mice were injected with monoclonal anti-collagen antibody cocktail followed by lipopolysaccharide to induce arthritis. HMGB1 and vascular endothelial growth factor (VEGF) were over-expressed in the areas of the synovium where more inflammation and neoangiogenesis were present. The selective blockade of HMGB1 or VEGF resulted alternatively in a lower severity of arthritis evaluated by the arthritis index. Furthermore, exogenous HMGB1 administration caused a worsening of arthritis, associated with VEGF up-regulation and increased synovial angiogenesis. The selective inhibition of VEGF also resulted in no induction of arthritis in mice receiving exogenous HMGB1. Cytokine enzyme-linked immunosorbent assay (ELISA) analyses performed on peripheral blood and synovial fluid demonstrated a significant reduction of interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)- in mice where HMGB1 and VEGF pathways were blocked. Interestingly, the selective blockade of HMGB1 and VEGF resulted in an increase of the peripheral IL-17A concentration. The development of arthritis mediated by HMGB1 and the synovial angiogenesis can be blocked by inhibiting the VEGF activity. The proinflammatory and proangiogenic cytokine IL-17A was increased when HMGB1 is inhibited, but the synovial angiogenesis was nevertheless reduced in this model of arthritis. Taken together, these findings shed new light on the role of this nuclear protein in the pathogenesis of arthritis in an RA-like model.