Experimental Immunology, University of Amsterdam, Amsterdam, The Netherlands.
Ann Rheum Dis. 2012 Aug;71(8):1402-10. doi: 10.1136/annrheumdis-2011-200718. Epub 2012 Jun 22.
Angiopoietin (Ang)-1 and Ang-2, and their shared receptor Tie2, are expressed in rheumatoid arthritis (RA) synovial tissue, but the cellular targets of Ang signalling and the relative contributions of Ang-1 and Ang-2 to arthritis are poorly understood.
To determine the cellular targets of Ang signalling in RA synovial tissue, and the effects of Ang-2 neutralisation in murine collagen-induced arthritis (CIA).
RA and psoriatic arthritis (PsA) synovial biopsies were examined for expression of Tie2 and activated phospho (p)-Tie2 by quantitative immunohistochemistry and immunofluorescent double staining. Human monocyte and macrophage Tie2 expression was determined by flow cytometry and quantitative PCR. Regulation of macrophage intracellular signalling pathways and gene expression were examined by immunoblotting and ELISA. CIA was assessed in mice treated with saline, control antibody, prednisolone or neutralising anti-Ang-2 antibody.
Expression of synovial Tie2 and p-Tie2 was similar in RA and PsA. Tie2 activation in RA patient synovial tissue was predominantly localised in synovial macrophages and was expressed by human macrophage. Ang-1 and Ang-2 stimulated activation of multiple intracellular signalling pathways, and cooperated with tumour necrosis factor to induce macrophage interleukin 6 and macrophage inflammatory protein 1α production. Ang-2 selectively suppressed macrophage thrombospondin-2 production. Ang-2 neutralisation significantly decreased disease severity, synovial inflammation, neo-vascularisation and joint destruction in established CIA.
The authors identify synovial macrophages as primary targets of Ang signalling in RA, and demonstrate that Ang-2 promotes the pro-inflammatory activation of human macrophages. Ang-2 makes requisite contributions to pathology in CIA, indicating that targeting Ang-2 may be of therapeutic benefit in the treatment of RA.
血管生成素 (Ang)-1 和 Ang-2 及其共同受体 Tie2 在类风湿关节炎 (RA) 滑膜组织中表达，但 Ang 信号的细胞靶点以及 Ang-1 和 Ang-2 对关节炎的相对贡献尚不清楚。
确定 RA 滑膜组织中 Ang 信号的细胞靶点，以及 Ang-2 中和在小鼠胶原诱导性关节炎 (CIA) 中的作用。
通过定量免疫组织化学和免疫荧光双重染色检查 RA 和银屑病关节炎 (PsA) 滑膜活检中 Tie2 和激活的磷酸化 (p)-Tie2 的表达。通过流式细胞术和定量 PCR 确定人单核细胞和巨噬细胞 Tie2 的表达。通过免疫印迹和 ELISA 研究巨噬细胞细胞内信号通路和基因表达的调节。用生理盐水、对照抗体、泼尼松龙或中和抗 Ang-2 抗体治疗 CIA 小鼠，并评估 CIA。
RA 和 PsA 滑膜中的 Tie2 和 p-Tie2 表达相似。RA 患者滑膜组织中 Tie2 的激活主要定位于滑膜巨噬细胞，并且由人巨噬细胞表达。Ang-1 和 Ang-2 刺激多种细胞内信号通路的激活，并与肿瘤坏死因子合作诱导巨噬细胞白细胞介素 6 和巨噬细胞炎症蛋白 1α 的产生。Ang-2 选择性抑制巨噬细胞血小板反应蛋白-2 的产生。Ang-2 中和显著降低了 CIA 中的疾病严重程度、滑膜炎症、新生血管形成和关节破坏。
作者确定 RA 中滑膜巨噬细胞为 Ang 信号的主要靶点，并证明 Ang-2 促进了人巨噬细胞的促炎激活。Ang-2 对 CIA 的病理学有必要的贡献，表明靶向 Ang-2 可能对 RA 的治疗有益。
