Chemokine CXCL13 mediates orofacial neuropathic pain via CXCR5/ERK pathway in the trigeminal ganglion of mice.
Chemokine CXCL13 mediates orofacial neuropathic pain via CXCR5/ERK pathway in the trigeminal ganglion of mice.
复制标题
趋化因子CXCL13通过CXCR5/ERK通路介导小鼠三叉神经节口面神经病理性疼痛
DOI：
10.1186/s12974-016-0652-1
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发表时间：
2016-07-11
影响因子：
9.3
通讯作者：
Gao YJ
中科院分区：
文献类型：
--
作者：
Zhang Q;Cao DL;Zhang ZJ;Jiang BC;Gao YJ
研究背景三叉神经损伤引起的神经病理性疼痛是一种严重的慢性口面部疼痛综合征。脊髓趋化因子CXCL 13及其受体CXCR 5在脊神经结扎引起的神经病理性疼痛的发病机制中起着关键作用。三叉神经节（TG）中的CXCL 13/CXCR 5是否以及如何介导口面疼痛（orofacial pain. Methodspartial infrared nerve ligation，pIONL）尚不清楚。免疫荧光染色和western blot检测TG中ATF 3、CXCL 13、CXCR 5和磷酸化细胞外信号调节激酶（pERK）的表达。通过行为测试检测靶向CXCL 13或CXCR 5的shRNA对疼痛超敏性的影响。通过shRNA慢病毒抑制CXCL 13或CXCR 5减弱pIONL诱导的机械性异常性疼痛。此外，在Cxcr 5 −/−小鼠中，pIONL诱导的神经病理性疼痛和TG中ERK的激活减少。此外，MEK抑制剂（PD 98059）减轻机械性异常性疼痛并减少pIONL诱导的TNF-α和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诱导的口面疼痛。最后，TG内注射CXCL 13诱导了机械性异常性疼痛，增加了WT小鼠TG中ERK的激活以及TNF-α和IL-1β的产生，但在Cxcr 5 −/−小鼠中没有。PD 98059、依那西普或双醋瑞因可部分阻断CXCL 13诱导的机械性痛觉超敏，PD 98059还可降低CXCL 13诱导的TNF-α和IL-1β上调。靶向三叉神经节内的CXCL 13/CXCR 5/ERK/TNF-α和IL-1β通路可能为口面神经病理性疼痛提供有效的治疗。
BackgroundTrigeminal 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.MethodsThe 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.ResultspIONL 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 inCxcr5−/−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 inCxcr5−/−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.ConclusionsCXCL13 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.