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Immunomodulatory oligonucleotides inhibit neutrophil migration by decreasing the surface expression of interleukin-8 and leukotriene B4 receptors

机译:免疫调节性寡核苷酸通过降低白细胞介素8和白三烯B4受体的表面表达来抑制中性粒细胞迁移

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摘要

Neutrophils play important roles in many inflammatory diseases. The migration of neutrophils to the inflammatory site is tightly regulated by specific chemokines, of which interleukin-8 (IL-8) and leukotriene B4 (LTB4) constitute key mediators by binding to the surface receptors CXCR1/2 and BLT1, respectively. Oligonucleotides (ODN) containing CpG motifs mediate potent immunomodulatory effects through binding to Toll-like receptor 9. So far, knowledge on how ODN can affect neutrophil migration during inflammation is lacking. This study demonstrates that several novel CpG ODN significantly down-regulate the surface expression of CXCR1/2 and BLT1. In addition, the ODN significantly blocked IL-8-induced and LTB4-induced neutrophil migration in vitro, as well as leucocyte migration in vivo demonstrated in mice by intravital microscopy and in a model of airway inflammation. The down-regulation of CXCR1 is rapid, occurring 15 min after ODN stimulation, and can be mediated through an endosomally independent mechanism. Inhibition of the IL-8 and LTB4 pathways may provide new opportunities of therapeutic intervention using ODN to reduce neutrophil infiltration during inflammation.
机译:中性粒细胞在许多炎性疾病中起重要作用。中性粒细胞向炎症部位的迁移受到特定趋化因子的严格调控,其中白介素8(IL-8)和白三烯B4(LTB4)通过分别与表面受体CXCR1 / 2和BLT1结合而构成关键介体。含有CpG基序的寡核苷酸(ODN)通过与Toll样受体9结合来介导有效的免疫调节作用。到目前为止,尚缺乏关于ODN如何在炎症过程中影响中性粒细胞迁移的知识。这项研究表明,几种新颖的CpG ODN显着下调CXCR1 / 2和BLT1的表面表达。此外,ODN显着阻断了体外IL-8诱导和LTB4诱导的嗜中性白细胞迁移,以及通过活体显微镜和小鼠气道炎症模型证明的体内白细胞迁移。 CXCR1的下调很快,发生在ODN刺激后15分钟,并且可以通过内体独立机制介导。 IL-8和LTB4途径的抑制可提供使用ODN减少炎症过程中嗜中性粒细胞浸润的治疗干预的新机会。

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