Spinal IL-33/ ST2 Signaling Contributes to Neuropathic Pain via Neuronal CaMKII- CREB and Astroglial JAK2-STAT3 Cascades in Mice
Spinal IL-33/ ST2 Signaling Contributes to Neuropathic Pain via Neuronal CaMKII- CREB and Astroglial JAK2-STAT3 Cascades in Mice
复制标题
小鼠中脊髓 IL-33/ST2 信号传导通过神经元 CaMKII-CREB 和星形胶质细胞 JAK2-STAT3 级联导致神经性疼痛
DOI：
10.1097/aln.0000000000000850
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发表时间：
2015-11-01
期刊：
影响因子：
8.8
通讯作者：
Wang, Yan-Qing
中科院分区：
文献类型：
--
作者：
Liu, Shenbin;Mi, Wen-Li;Wang, Yan-Qing
背景：新的证据表明，神经损伤引发的神经炎症和免疫反应，以促炎细胞因子上调为证据，参与了神经病理性疼痛的发展。本研究探讨了脊髓白介素33及其受体ST2在备用神经损伤(SNI)诱导的神经病理性疼痛中的作用。方法：采用von Frey试验和丙酮试验评价神经病理性疼痛行为(n=8~12)，Western印迹(n=4~6)、免疫组织化学、实时定量聚合酶链式反应(n=5)和Bio-Plex(n=5)分析其分子机制。结果：鞘内注射ST2中和抗体或ST2基因敲除(ST2(-/-))可显著减轻SNI诱导的机械性和冷痛性痛觉。在SNI后第7天，脊髓IL-33和ST2的表达分别增加了255.8和27.3%和266.4+/-83.5%(平均+/-SD)。机制研究表明，SNI后脊髓N-甲基-d-天冬氨酸(NMDA)受体亚单位1的表达增加可被ST2抗体或ST2(-/-)所降低。非竞争性NMDA拮抗剂MK-801可逆转重组IL-33对幼鼠伤害行为的诱导。给予ST2抗体或ST2(-/-)显著抑制SNI后星形胶质细胞Janus kinase2(JAK2)信号转导和转录激活子3(STAT3)级联和神经元钙钙调素依赖性激酶II(CaMKII)-环磷酸腺苷反应元件结合蛋白(CREB)级联的激活。此外，鞘内注射CaMKII抑制剂KN-93或JAK2-STAT3级联抑制剂AG490可减弱重组IL-33诱导的伤害性行为和NMDA亚单位1的上调。结论：脊髓IL-33/ST2信号通路通过激活星形胶质细胞JAK2-STAT3级联和神经元CaMKII-CREB级联而参与神经病理性疼痛。
Background: Emerging evidence indicates that nerve damage-initiated neuroinflammation and immune responses, which are evidenced by the up-regulation of proinflammatory cytokines, contribute to the development of neuropathic pain. This study investigated the role of spinal interleukin (IL)-33 and its receptor ST2 in spared nerve injury (SNI)-induced neuropathic pain.Methods: The von Frey test and acetone test were performed to evaluate neuropathic pain behaviors (n = 8 to 12), and Western blot (n = 4 to 6), immunohistochemistry, real-time polymerase chain reaction (n = 5), and Bio-Plex (n = 5) assays were performed to understand the molecular mechanisms.Results: Intrathecal administration of ST2-neutralizing antibody or ST2 gene knockout (ST2(-/-)) significantly attenuated the SNI-induced mechanical and cold allodynia. On the 7th day after SNI, the expression of spinal IL-33 and ST2 was increased by 255.8 27.3% and 266.4 +/- 83.5% (mean +/- SD), respectively. Mechanistic studies showed that the increased expression of the spinal N-methyl-d-aspartate (NMDA) receptor subunit 1 after SNI was reduced by ST2 antibody administration or ST2(-/-). The induction of nociceptive behaviors in naive mice due to recombinant IL-33 was reversed by the noncompetitive NMDA antagonist MK-801. ST2 antibody administration or ST2(-/-) markedly inhibited the increased activation of the astroglial janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) cascade and the neuronal calcium-calmodulin-dependent kinase II (CaMKII)-cyclic adenosine monophosphate response element-binding protein (CREB) cascade after SNI. Moreover, intrathecal pretreatment with the CaMKII inhibitor KN-93 or the JAK2-STAT3 cascade inhibitor AG490 attenuated recombinant IL-33-induced nociceptive behaviors and NMDA subunit 1 up-regulation in naive mice.Conclusion: Spinal IL-33/ST2 signaling contributes to neuropathic pain by activating the astroglial JAK2-STAT3 cascade and the neuronal CaMKII-CREB cascade.