Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, Zentrums für Arzneimittelforschung Entwicklung und Sicherheit, Klinikum der Goethe-Universität Frankfurt, Frankfurt, Germany;
Universität Würzburg, Institut für Experimentelle Biomedizin, Universitätsklinikum und Rudolf-Virchow-Zentrum für Experimentelle Biomedizin, Würzburg, Germany; and.
J Leukoc Biol. 2014 Jul;96(1):133-42. doi: 10.1189/jlb.3A1213-628R. Epub 2014 Feb 20.
Inflammatory pain is based on stimulation and sensitization of peripheral endings of sensory neurons (nociceptors) by pronociceptive mediators. These mediators can be released by resident cells, as well as invading immune cells. Although neutrophils are known to release various mediators, which can stimulate or sensitize nociceptors, the extent of their contribution to nociceptive responses is unclear. Here, we studied the contribution of neutrophils to zymosan-induced inflammatory pain, which is characterized by an early recruitment of high numbers of neutrophils. Surprisingly, antibody-mediated neutrophil depletion caused a complete loss of edema formation but had no effect on mechanical pain thresholds. Blockage of the interaction between neutrophils and platelets or endothelial cells using antibodies directed against CD11b and CD162 reduced neutrophil recruitment to the site of inflammation. Again, the treatment decreased zymosan-induced edemas without altering mechanical pain thresholds. Also, HLB-219 mice, which have five to 10 times less platelets than WT mice, showed reduced neutrophil recruitment to the site of inflammation and decreased edema sizes, whereas, again, mechanical thresholds were unaltered. The effects observed in HLB-219 mice were relatively small and not reproduced in vWF-deficient mice or after antibody-mediated blockage of GPIbα. Flow chamber and transmigration assays showed that platelets were not necessary for neutrophil adhesion to endothelial cells but increased their transmigration. Taken together, zymosan-induced mechanical allodynia is, in contrast to edema formation, independent of neutrophils, and recruitment of neutrophils is only partly influenced by interactions with platelets.
炎症性疼痛是基于感觉神经元（伤害感受器）的外周末梢受到 pronociceptive 介质的刺激和敏化。这些介质可以由驻留细胞以及入侵的免疫细胞释放。虽然已知中性粒细胞会释放各种介质，这些介质可以刺激或敏化伤害感受器，但它们对伤害性反应的贡献程度尚不清楚。在这里，我们研究了中性粒细胞对酵母聚糖诱导的炎症性疼痛的贡献，这种疼痛的特征是早期大量中性粒细胞的募集。令人惊讶的是，抗体介导的中性粒细胞耗竭导致水肿形成完全丧失，但对机械性疼痛阈值没有影响。使用针对 CD11b 和 CD162 的抗体阻断中性粒细胞与血小板或内皮细胞之间的相互作用，减少了炎症部位的中性粒细胞募集。同样，这种治疗减少了酵母聚糖诱导的水肿，而不改变机械性疼痛阈值。此外，HLB-219 小鼠的血小板数量比 WT 小鼠少 5 到 10 倍，它们表现出炎症部位中性粒细胞募集减少和水肿体积减小，而机械阈值没有改变。在 HLB-219 小鼠中观察到的效果相对较小，并且在 vWF 缺陷型小鼠或通过抗体介导的 GPIbα 阻断后没有重现。流动室和迁移实验表明，血小板对于中性粒细胞与内皮细胞的黏附不是必需的，但增加了它们的迁移。总之，与水肿形成相反，酵母聚糖诱导的机械性痛觉过敏独立于中性粒细胞，而中性粒细胞的募集仅部分受与血小板的相互作用影响。
