Interleukin-17 Sensitizes Joint Nociceptors to Mechanical Stimuli and Contributes to Arthritic Pain Through Neuronal Interleukin-17 Receptors in Rodents
Interleukin-17 Sensitizes Joint Nociceptors to Mechanical Stimuli and Contributes to Arthritic Pain Through Neuronal Interleukin-17 Receptors in Rodents
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DOI：
10.1002/art.37695
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发表时间：
2012-12-01
影响因子：
--
通讯作者：
Schaible, Hans-Georg
中科院分区：
文献类型：
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作者：
Richter, Frank;Natura, Gabriel;Schaible, Hans-Georg
客观的。白细胞介素-17 (IL-17) 被认为是一种促炎细胞因子，但神经元 IL-17 受体是否有助于关节炎疼痛的产生尚不清楚。本研究旨在探讨IL-17A是否作用于神经元、是否使关节伤害感受器敏感以及IL-17的中和是否具有抗伤害作用。方法。我们记录了关节内注射 IL-17A 后大鼠关节伤害感受器的动作电位。我们研究了大鼠背根神经节（DRG）中IL-17A受体的表达，探讨了IL-17A对培养的大鼠DRG神经元信号通路的影响，并利用膜片钳记录监测了IL-17A兴奋性的变化。我们测试了 IL-17 抗体是否影响抗原诱导关节炎 (AIA) 小鼠的疼痛行为。结果。向大鼠膝关节单次注射 IL-17A 会引起关节伤害性 C 纤维对机械刺激的缓慢发展且持久的敏感性，并且中和肿瘤坏死因子 α 或 IL-6 不会减弱这种敏感性。 IL-17A 受体在大多数大鼠 DRG 神经元（初级感觉神经元的细胞体）中可见。在分离培养的大鼠 DRG 神经元中，IL-17A 引起蛋白激酶 B 和 ERK 快速磷酸化，并迅速增强兴奋性。在膝部患有单侧 AIA 的小鼠中，IL-17 抗体改善了同侧爪子的防护评分并减少了继发性机械痛觉过敏。结论。我们的研究结果表明，IL-17A 有可能通过靶向伤害性神经元中的 IL-17 受体而充当疼痛介质，并且这些受体特别参与炎症诱发的机械痛觉过敏。
Objective. Interleukin-17 (IL-17) is considered a proinflammatory cytokine, but whether neuronal IL-17 receptors contribute to the generation of arthritic pain is unknown. This study was undertaken to explore whether IL-17A acts on neurons, whether it sensitizes joint nociceptors, and whether neutralization of IL-17 is antinociceptive.Methods. We recorded action potentials from rat joint nociceptors after intraarticular injection of IL-17A. We studied the expression of the IL-17A receptor in the rat dorsal root ganglia (DRG), explored the effect of IL-17A on signaling pathways in cultured rat DRG neurons, and using patch clamp recordings, monitored changes of excitability by IL-17A. We tested whether an antibody to IL-17 influences pain behaviors in mice with antigen-induced arthritis (AIA).Results. A single injection of IL-17A into the rat knee joint elicited a slowly developing and long-lasting sensitization of nociceptive C fibers of the joint to mechanical stimuli, which was not attenuated by neutralizing tumor necrosis factor alpha or IL-6. The IL-17A receptor was visualized in most rat DRG neurons, the cell bodies of primary sensory neurons. In isolated and cultured rat DRG neurons, IL-17A caused rapid phosphorylation of protein kinase B and ERK, and it rapidly enhanced excitability. In mice with unilateral AIA in the knee, an antibody against IL-17 improved the guarding score and reduced secondary mechanical hyperalgesia at the ipsilateral paw.Conclusion. Our findings indicate that IL-17A has the potential to act as a pain mediator by targeting IL-17 receptors in nociceptive neurons, and these receptors are particularly involved in inflammation-evoked mechanical hyperalgesia.