Up-regulation of interleukin-23 induces persistent allodynia via CX3CL1 and interleukin-18 signaling in the rat spinal cord after tetanic sciatic stimulation
Up-regulation of interleukin-23 induces persistent allodynia via CX3CL1 and interleukin-18 signaling in the rat spinal cord after tetanic sciatic stimulation
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DOI：
10.1016/j.bbi.2013.12.011
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发表时间：
2014-03-01
影响因子：
15.1
通讯作者：
Zhang, Yu-Qiu
中科院分区：
文献类型：
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作者：
Bian, Chao;Wang, Zhe-Chen;Zhang, Yu-Qiu
坐骨神经（TSS）的强直刺激会引起大鼠坐骨神经损伤和持久的疼痛超敏反应，并且与脊髓胶质细胞激活和促炎细胞因子释放有关。在本研究中，我们发现脊髓白细胞介素 (IL)-23 及其受体 IL-23R 对于 TSS 后机械性异常性疼痛的发生至关重要。在脊髓背角，星形胶质细胞中表达IL-23和IL-23R，并且这种表达在TSS后显着增加。抑制 IL-23 信号可减弱 TSS 诱导的异常性疼痛，并减少神经胶质纤维酸性蛋白（GFAP，一种星形细胞标记物）的诱导。相反，鞘内递送IL-23引起持续性异常性疼痛。与 IL-23 信号传导类似，TSS 后在脊髓背角中同时观察到 IL-18 及其受体 IL-18R 以及 CX3CL1 及其受体 CX3CR1 的增加。有趣的是，IL-18和CX3CR1仅在小胶质细胞中表达，而IL-18R主要位于星形胶质细胞中。相反，CX3CL1 主要在神经元中表达，其次在星形胶质细胞中表达。 CX3CL1 和 IL-18 信号传导的功能性抑制可减轻 TSS 诱导的异常性疼痛并抑制 IL-23 和 IL-23R 的上调。 CX3CR1 和 IL-18R 的激活诱导了与 TSS 后观察到的类似的行为和生化变化。这些结果表明脊髓中 CX3CL1、IL-18 和 IL-23 信号传导之间的相互作用在异常性疼痛的发生中起着关键作用。因此，中断这种趋化因子-细胞因子网络可能为神经性疼痛提供一种新的治疗策略。 (C) 2013 Elsevier Inc. 保留所有权利。
Tetanic stimulation of the sciatic nerve (TSS) induces sciatic nerve injury and long-lasting pain hypersensitivity in rats, and spinal glial activation and proinflammatory cytokines releases are involved. In the present study, we showed that spinal interleukin (IL)-23 and its receptor, IL-23R, are crucial for the development of mechanical allodynia after TSS. In the spinal dorsal horn, both IL-23 and IL-23R are expressed in astrocytes, and this expression is substantially increased after TSS. Inhibition of IL-23 signaling attenuated TSS-induced allodynia and decreased the induction of glial fibrillary acidic protein (GFAP, an astrocytic marker). Conversely, intrathecally delivered IL-23 induced a persistent allodynia. Similar to IL-23 signaling, an increase in IL-18 and its receptor, IL-18R, as well as CX3CL1 and its receptor, CX3CR1, was simultaneously observed in the spinal dorsal horn after TSS. Interestingly, IL-18 and CX3CR1 were exclusively expressed in microglia, while IL-18R was mainly localized in astrocytes. In contrast, CX3CL1 was predominately expressed in neurons and secondarily in astrocytes. The functional inhibition of CX3CL1 and IL-18 signaling attenuated TSS-induced allodynia and suppressed IL-23 and IL-23R upregulation. Activation of CX3CR1 and IL-18R induced similar behavioral and biochemical changes to those observed after TSS. These results indicate that the interaction among CX3CL1, IL-18 and IL-23 signaling in the spinal cord plays a critical role in the development of allodynia. Thus, interrupting this chemokine-cytokine network might provide a novel therapeutic strategy for neuropathic pain. (C) 2013 Elsevier Inc. All rights reserved.