The chemokine receptors CXCR1/CXCR2 modulate antigen-induced arthritis by regulating adhesion of neutrophils to the synovial microvasculature
The chemokine receptors CXCR1/CXCR2 modulate antigen-induced arthritis by regulating adhesion of neutrophils to the synovial microvasculature
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DOI：
10.1002/art.23622
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发表时间：
2008-08-01
影响因子：
--
通讯作者：
Teixeira, Mauro M.
中科院分区：
文献类型：
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作者：
Coelho, Fernanda M.;Pinho, Vanessa;Teixeira, Mauro M.
Objective.趋化因子受体CXCR 1和CXCR 2在几种炎症模型中介导中性粒细胞募集和嗜中性粒细胞依赖性损伤中发挥作用。我们进行了这项研究，以调查这些受体介导的中性粒细胞粘附，随后的迁移，和嗜中性粒细胞依赖性高伤害性在海洋模型的单关节抗原诱导的关节炎（AIA）的作用。通过将抗原施用到先前免疫的小鼠的膝关节中来诱导AIA。进行活体显微镜研究以评估白细胞滚动和粘附。使用电子压力计研究机械性痛觉过敏。通过计数滑膜腔中的中性粒细胞和测定髓过氧化物酶活性来测量组织中的中性粒细胞积聚。肿瘤坏死因子α（TNF α）和趋化因子CXCL 1和CXCL 2的水平通过酶联免疫吸附测定进行定量。进行组织学分析以评估关节炎和白细胞浸润的严重程度。免疫小鼠的抗原攻击诱导TNF α、CXCL 1和CXCL 2的产生，还导致中性粒细胞募集、白细胞滚动和粘附以及高伤害感受。用瑞帕新或DF 2162（CXCR 1/CXCR 2的变构抑制剂）治疗减少了中性粒细胞募集，该作用与中性粒细胞粘附的显著抑制相关。药物治疗还抑制了TNF α的产生、痛觉过敏和组织中疾病的总体严重程度。阻断CXCR 1/CXCR 2受体可通过抑制中性粒细胞粘附于滑膜微血管来抑制中性粒细胞募集。因此，局部细胞因子的产生减少，高伤害感受减少，以及组织中整体疾病的减轻。这些研究表明，在关节炎的治疗中，CXCR 1/CXCR 2受体信号转导的调节具有潜在的治疗作用。
Objective. The chemokine receptors CXCR1 and CXCR2 play a role in mediating neutrophil recruitment and neutrophil-dependent injury in several models of inflammation. We undertook this study to investigate the role of these receptors in mediating neutrophil adhesion, subsequent migration, and neutrophil-dependent hypernociception in a marine model of monarticular antigen-induced arthritis (AIA).Methods. AIA was induced by administration of antigen into the knee joint of previously immunized mice. Intravital microscopy studies were performed to assess leukocyte rolling and adhesion. Mechanical hypernociception was investigated using an electronic pressure meter. Neutrophil accumulation in the tissue was measured by counting neutrophils in the synovial cavity and assaying myeloperoxidase activity. Levels of tumor necrosis factor alpha (TNF alpha) and the chemokines CXCL1 and CXCL2 were quantified by enzyme-linked immunosorbent assay. Histologic analysis was per-formed to evaluate the severity of arthritis and leukocyte infiltration.Results. Antigen challenge in immunized mice induced production of TNF alpha, CXCL1, and CXCL2 and also resulted in neutrophil recruitment, leukocyte rolling and adhesion, and hypernociception. Treatment with reparixin or DF2162 (allosteric inhibitors of CXCR1/CXCR2) decreased neutrophil recruitment, an effect that was associated with marked inhibition of neutrophil adhesion. Drug treatment also inhibited TNFa production, hypernociception, and the overall severity of the disease in the tissue.Conclusion. Blockade of CXCR1/CXCR2 receptors inhibits neutrophil recruitment by inhibiting the adhesion of neutrophils to synovial microvessels. As a consequence, there is decreased local cytokine production and reduced hypernociception, as well as ameloriation of overall disease in the tissue. These studies suggest a potential therapeutic role for the modulation of CXCR1/CXCR2 receptor signaling in the treatment of arthritis.