CXCR2-specific chemokines mediate leukotriene B4-dependent recruitment of neutrophils to inflamed joints in mice with antigen-induced arthritis
CXCR2-specific chemokines mediate leukotriene B4-dependent recruitment of neutrophils to inflamed joints in mice with antigen-induced arthritis
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DOI：
10.1002/art.23597
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发表时间：
2008-07-01
影响因子：
--
通讯作者：
Cunha, Fernando Q.
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文献类型：
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作者：
Grespan, Renata;Fukada, Sandra Y.;Cunha, Fernando Q.
客观的。研究实验性关节炎以及人类炎症性滑膜炎中性粒细胞迁移到关节腔的机制。方法。甲基化牛血清白蛋白（mBSA）在小鼠体内产生抗原诱导关节炎（AIA）。使用迁移测定和组织学分析来评估中性粒细胞向膝关节的募集。通过酶联免疫吸附测定法测量炎症介质的水平。在体内使用抗体和药物抑制剂来确定特定疾病介质的作用。对类风湿性关节炎 (RA) 或骨关节炎患者的滑液组织和滑液样本进行 CXCL1 和 CXCL5 表达评估。结果。关节炎小鼠的关节中表达高水平的 CXCL1、CXCL5 和白三烯 B-4 (LTB4)。证实了它们各自的功能作用，repertaxin（一种 CXCR1/CXCR2 受体拮抗剂）、抗 CXCL1 抗体、抗 CXCL5 抗体和 MK886（一种白三烯合成抑制剂）减少了 mBSA 诱导的中性粒细胞向膝关节的迁移。 Repertaxin 减少了关节组织中 LTB4 的产生，并且 CXCL1 或 CXCL5 诱导的中性粒细胞募集被 MK886 抑制，表明存在顺序机制。滑液中 CXCL1 和 CXCL5 的水平均升高，并由 RA 滑膜组织在体外释放。此外，用CXCL1或CXCL5刺激的RA滑液中性粒细胞释放大量LTB4。结论。我们的数据表明 CXCL1、CXCL5 和 LTB4 在 AIA 中的中性粒细胞迁移中依次起作用。 RA 患者滑膜室中 CXCL1 和 CXCL5 水平升高提供了强有力的比较数据，表明该机制在炎症性关节疾病中发挥作用。总之，这些结果表明抑制。 CXCL1、CXCL5 或 LTB4 可能代表 RA 的潜在治疗策略。
Objective. To investigate the mechanism underlying neutrophil migration into the articular cavity in experimental arthritis and, by extension, human-inflammatory synovitis.Methods. Antigen-induced arthritis (AIA) was generated in mice with methylated bovine serum albumin (mBSA). Migration assays and histologic analysis were used to evaluate neutrophil recruitment to knee joints. Levels of inflammatory mediators were measured by enzyme-linked immunosorbent assay. Antibodies and pharmacologic inhibitors were used in vivo to determine the role of specific disease mediators. Samples of synovial tissue and synovial fluid from rheumatoid arthritis (RA) or osteoarthritis patients were evaluated for CXCL1 and CXCL5 expression.Results. High levels of CXCL1, CXCL5, and leukotriene B-4 (LTB4) were expressed in the joints of arthritic mice. Confirming their respective functional roles, repertaxin (a CXCR1/CXCR2 receptor antagonist), anti-CXCL1 antibody, anti-CXCL5 antibody, and MK886 (a leukotriene synthesis inhibitor) reduced mBSA-induced neutrophil migration to knee joints. Repertaxin reduced LTB4 production in joint tissue, and neutrophil recruitment induced by CXCL1 or CXCL5 was inhibited by MK886, suggesting a sequential mechanism. Levels of both CXCL1 and CXCL5 were elevated in synovial fluid and were released in vitro by RA synovial tissues. Moreover, RA synovial fluid neutrophils stimulated with CXCL1 or CXCL5 released significant amounts of LTB4.Conclusion. Our data implicate CXCL1, CXCL5, and LTB4, acting sequentially, in neutrophil migration in AIA. Elevated levels of CXCL1 and CXCL5 in the synovial compartment of RA patients provide robust comparative data indicating that this mechanism plays a role in inflammatory joint disease. Together, these results suggest that inhibition of. CXCL1, CXCL5, or LTB4 may represent a potential therapeutic strategy in RA.