趋化因子CXCL13通过CXCR5/ERK途径介导小鼠三叉神经节中的口面部神经性疼痛。
Chemokine CXCL13 mediates orofacial neuropathic pain via CXCR5/ERK pathway in the trigeminal ganglion of mice.
作者信息
Zhang Qian, Cao De-Li, Zhang Zhi-Jun, Jiang Bao-Chun, Gao Yong-Jing
机构信息
Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Seyuan Road, Nantong, Jiangsu, 226019, China.
Department of Human Anatomy, School of Medicine, Nantong University, Nantong, Jiangsu, 226001, China.
出版信息
J Neuroinflammation. 2016 Jul 11;13(1):183. doi: 10.1186/s12974-016-0652-1.
BACKGROUND
Trigeminal nerve damage-induced neuropathic pain is a severely debilitating chronic orofacial pain syndrome. Spinal chemokine CXCL13 and its receptor CXCR5 were recently demonstrated to play a pivotal role in the pathogenesis of spinal nerve ligation-induced neuropathic pain. Whether and how CXCL13/CXCR5 in the trigeminal ganglion (TG) mediates orofacial pain are unknown.
METHODS
The partial infraorbital nerve ligation (pIONL) was used to induce trigeminal neuropathic pain in mice. The expression of ATF3, CXCL13, CXCR5, and phosphorylated extracellular signal-regulated kinase (pERK) in the TG was detected by immunofluorescence staining and western blot. The effect of shRNA targeting on CXCL13 or CXCR5 on pain hypersensitivity was checked by behavioral testing.
RESULTS
pIONL induced persistent mechanical allodynia and increased the expression of ATF3, CXCL13, and CXCR5 in the TG. Inhibition of CXCL13 or CXCR5 by shRNA lentivirus attenuated pIONL-induced mechanical allodynia. Additionally, pIONL-induced neuropathic pain and the activation of ERK in the TG were reduced in Cxcr5 (-/-) mice. Furthermore, MEK inhibitor (PD98059) attenuated mechanical allodynia and reduced TNF-α and IL-1β upregulation induced by pIONL. TNF-α inhibitor (Etanercept) and IL-1β inhibitor (Diacerein) attenuated pIONL-induced orofacial pain. Finally, intra-TG injection of CXCL13 induced mechanical allodynia, increased the activation of ERK and the production of TNF-α and IL-1β in the TG of WT mice, but not in Cxcr5 (-/-) mice. Pretreatment with PD98059, Etanercept, or Diacerein partially blocked CXCL13-induced mechanical allodynia, and PD98059 also reduced CXCL13-induced TNF-α and IL-1β upregulation.
CONCLUSIONS
CXCL13 and CXCR5 contribute to orofacial pain via ERK-mediated proinflammatory cytokines production. Targeting CXCL13/CXCR5/ERK/TNF-α and IL-1β pathway in the trigeminal ganglion may offer effective treatment for orofacial neuropathic pain.
背景
三叉神经损伤所致神经性疼痛是一种严重致残的慢性口面部疼痛综合征。脊髓趋化因子CXCL13及其受体CXCR5最近被证明在脊髓神经结扎诱导的神经性疼痛发病机制中起关键作用。三叉神经节（TG）中的CXCL13/CXCR5是否以及如何介导口面部疼痛尚不清楚。
方法
采用部分眶下神经结扎（pIONL）诱导小鼠三叉神经性疼痛。通过免疫荧光染色和蛋白质印迹法检测TG中活化转录因子3（ATF3）、CXCL13、CXCR5和磷酸化细胞外信号调节激酶（pERK）的表达。通过行为测试检查靶向CXCL13或CXCR5的短发夹RNA（shRNA）对疼痛超敏反应的影响。
结果
pIONL诱导持续的机械性异常性疼痛，并增加TG中ATF3、CXCL13和CXCR5的表达。shRNA慢病毒抑制CXCL13或CXCR5可减轻pIONL诱导的机械性异常性疼痛。此外，Cxcr5基因敲除（-/-）小鼠中，pIONL诱导的神经性疼痛及TG中ERK的激活减弱。此外，丝裂原活化蛋白激酶/细胞外信号调节激酶激酶（MEK）抑制剂（PD98059）减轻机械性异常性疼痛，并降低pIONL诱导的肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）上调。TNF-α抑制剂（依那西普）和IL-1β抑制剂（双醋瑞因）减轻pIONL诱导的口面部疼痛。最后，向TG内注射CXCL13可诱导野生型（WT）小鼠机械性异常性疼痛，增加TG中ERK的激活以及TNF-α和IL-1β的产生，但在Cxcr5（-/-）小鼠中无此现象。用PD98059、依那西普或双醋瑞因预处理可部分阻断CXCL13诱导的机械性异常性疼痛，且PD98059还可降低CXCL13诱导的TNF-α和IL-1β上调。
结论
CXCL13和CXCR5通过ERK介导的促炎细胞因子产生促进口面部疼痛。靶向三叉神经节中的CXCL13/CXCR5/ERK/TNF-α和IL-1β通路可能为口面部神经性疼痛提供有效的治疗方法。
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