Epigenetic upregulation of CXCL 12 expression mediates antitubulin chemotherapeutics-induced neuropathic pain
Epigenetic upregulation of CXCL 12 expression mediates antitubulin chemotherapeutics-induced neuropathic pain
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CXCL 12 表达的表观遗传上调介导抗微管蛋白化疗药物诱导的神经性疼痛
DOI：
10.1097/j.pain.0000000000000805
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发表时间：
2017-04-01
期刊：
影响因子：
7.4
通讯作者：
Xin, Wen-Jun
中科院分区：
文献类型：
--
作者：
Xu, Ting;Zhang, Xiao-Long;Xin, Wen-Jun
临床上，微管靶向药物诱导的神经病理性疼痛阻碍了癌症患者的化疗。在此，我们发现应用紫杉醇或长春新碱增加脊髓背角神经元中CXCL 12的蛋白和mRNA表达以及微小兴奋性突触后电流（mEPSC）的频率和幅度。脊髓局部应用CXCL 12诱导伤害性突触传递的长时程增强，并增加mEPSC的振幅。使用转基因小鼠（CXCL 12（-/+））或中和抗体或siRNA抑制CXCL 12改善了mEPSC的增强和机械异常性疼痛。此外，紫杉醇和长春新碱均能增加表达CXCL 12的神经元中信号转导子和转录激活子3（STAT 3）的磷酸化和组蛋白H4的乙酰化。免疫沉淀和染色质免疫沉淀实验表明，抗微管蛋白化疗药物可增强STAT 3与CXCL 12基因启动子的结合以及STAT 3与p300的相互作用，并通过增加CXCL 12基因启动子中组蛋白H4的乙酰化而促进CXCL 12的转录。通过鞘内注射编码Cre和绿色荧光蛋白的腺相关病毒抑制STAT 3（flox/flox）小鼠或抑制剂S3 I-201抑制大鼠CXCL 12的升高，通过降低组蛋白H4的乙酰化。最后，阻断CXCR 4而非CXCR 7可改善紫杉醇或长春新碱诱导的机械性异常性疼痛。总之，这些结果表明，STAT 3和p300之间增强的相互作用介导了背角神经元中CXCL 12的表观遗传上调，这有助于抗微管蛋白化疗诱导的持续性疼痛。
Clinically, Microtubule-targeted agents-induced neuropathic pain hampers chemotherapeutics for patients with cancer. Here, we found that application of paclitaxel or vincristine increased the protein and mRNA expression of CXCL 12 and frequency and amplitude of miniature excitatory post synaptic currents (mEPSCs) in spinal dorsal horn neurons. Spinal local application of CXCL 12 induced the long-term potentiation of nociceptive synaptic transmission and increased the amplitude of mEPSCs. Inhibition of CXCL 12 using the transgenic mice (CXCL 12(-/+)) or neutralizing antibody or siRNA ameliorated the mEPSC's enhancement and mechanical allodynia. In addition, paclitaxel and vincristine both could increase the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the acetylation of histone H4 in the CXCL 12-expressing neurons. Immunoprecipitation and chromatin immunoprecipitation assays demonstrated that antitubulin chemotherapeutics increased the binding of STAT3 to the CXCL 12 gene promoter and the interaction between STAT3 and p300, and contributed to the enhanced transcription of CXCL 12 by increasing the acetylation of histone H4 in CXCL 12 gene promoter. Inhibition of STAT3 by intrathecal injection of adeno-associated virus encoding Cre and green fluorescent protein into STAT3(flox/flox) mice or inhibitor S3I-201 into rats suppressed the CXCL 12 upsurge by decreasing the acetylation of histone H4. Finally, blockade of CXCR4 but not CXCR7 ameliorated the paclitaxel-or vincristine-induced mechanical allodynia. Together, these results suggested that enhanced interaction between STAT3 and p300 mediated the epigenetic upregulation of CXCL 12 in dorsal horn neurons, which contributed to the antitubulin chemotherapeutics-induced persistent pain.