Medicity Research Laboratory, Turku, Finland.
Am J Pathol. 2012 Jul;181(1):141-50. doi: 10.1016/j.ajpath.2012.03.031. Epub 2012 May 27.
The suppressive role of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) complex-derived reactive oxygen species (ROS) in adaptive immunity-driven arthritis models is well established. In this study, we aimed to investigate the role of NOX2 complex-derived ROS in a model of innate immunity-driven arthritis and to identify the ROS-regulated innate receptors that control arthritis. We used collagen antibody-induced arthritis (CAIA), which is a T and B lymphocyte-independent model of the effector phase of arthritis and is induced by well-defined monoclonal arthritogenic antibodies and enhanced by injection of lipopolysaccharide (LPS). CAIA was induced in both wild-type and Ncf1 mutant mice that lack phagocyte oxidative burst, and stimulated with LPS and other agents to activate innate immune responses. We found that both LPS and lipomannan enhanced CAIA more potently in the presence of functional phagocyte ROS production than in its absence. The ROS-dependent enhancement of CAIA was regulated by TLR2, but not by TLR4 stimulation, and was driven by granulocytes, whereas macrophages did not contribute to the phenotype. In addition, we report that collagen-induced arthritis was not affected by the functionality of the TLR4. We report that TLR2 signaling as an important ROS-regulated proinflammatory pathway leads to severe neutrophil-dependent inflammation in murine CAIA and conclude that the TLR2 pathway is modulated by phagocyte ROS to stimulate the development of arthritis.
吞噬细胞烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（NOX2）复合物衍生的活性氧（ROS）在适应性免疫驱动的关节炎模型中具有抑制作用，这一作用已得到充分证实。在本研究中，我们旨在研究先天免疫驱动的关节炎模型中 NOX2 复合物衍生的 ROS 的作用，并确定控制关节炎的 ROS 调节的先天受体。我们使用胶原抗体诱导的关节炎（CAIA）作为一种 T 和 B 淋巴细胞非依赖性关节炎效应阶段模型，由明确的单克隆致关节炎抗体诱导，并通过注射脂多糖（LPS）增强。在缺乏吞噬细胞氧化爆发的 Ncf1 突变小鼠和野生型小鼠中诱导 CAIA，并刺激 LPS 和其他试剂以激活先天免疫反应。我们发现，与缺乏功能吞噬细胞 ROS 产生相比，LPS 和脂磷壁酸在存在功能性吞噬细胞 ROS 产生的情况下更能增强 CAIA。CAIA 的 ROS 依赖性增强受 TLR2 调节，但不受 TLR4 刺激调节，并且由粒细胞驱动，而巨噬细胞对表型没有贡献。此外，我们报告称，胶原诱导的关节炎不受 TLR4 功能的影响。我们报告称，TLR2 信号作为一种重要的 ROS 调节的促炎途径，导致鼠 CAIA 中严重的嗜中性粒细胞依赖性炎症，并得出结论，TLR2 途径受吞噬细胞 ROS 调节以刺激关节炎的发展。
