Upregulation of NLRP3 via STAT3-dependent histone acetylation contributes to painful neuropathy induced by bortezomib
Upregulation of NLRP3 via STAT3-dependent histone acetylation contributes to painful neuropathy induced by bortezomib
复制标题
通过 STAT3 依赖性组蛋白乙酰化上调 NLRP3 导致硼替佐米诱发的疼痛性神经病变
DOI：
10.1016/j.expneurol.2018.01.011
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发表时间：
2018-04-01
影响因子：
5.3
通讯作者：
Ma, Chao
中科院分区：
文献类型：
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作者：
Liu, Cui-Cui;Huang, Zhu-Xi;Ma, Chao
疼痛性神经病变作为化疗硼替佐米的严重副作用，是治疗中止的最常见原因。然而，硼替佐米给药导致疼痛性神经病变的机制仍不清楚。在本研究中，我们发现硼替佐米的应用显着增加了背根神经节（DRG）的NOD样受体家族pyrin domain containing 3（NLRP 3）和磷酸化信号转导和转录激活因子3（STAT 3）的表达。鞘内注射NLRP 3 siRNA可显著抑制硼替佐米诱导的机械性痛觉超敏反应，鞘内注射编码NLRP 3的重组腺相关病毒载体可显著降低幼稚大鼠的缩足阈值。此外，p-STAT 3的表达与NLRP 3阳性细胞共定位于DRG神经元，通过向STAT 3（flox/flox）小鼠鞘内注射AAV-Cre-GFP或抑制剂S3 I-201抑制STAT 3，可抑制NLRP 3的上调和硼替佐米诱导的机械性异常性疼痛。染色质免疫沉淀进一步发现硼替佐米增加了DRG神经元中NLRP 3启动子区域中STAT 3的募集以及组蛋白H3和H4的乙酰化。重要的是，通过使用S3 I-201或STAT 3的DRG局部缺陷抑制STAT 3活性也显著防止硼替佐米处理后NLRP 3启动子区域中上调的H3和H4乙酰化。总之，我们的研究结果表明，通过STAT 3依赖性组蛋白乙酰化上调DRG中的NLRP 3在硼替佐米诱导的机械异常性疼痛中起关键作用。
Painful neuropathy, as a severe side effect of chemotherapeutic bortezomib, is the most common reason for treatment discontinuation. However, the mechanism by which administration of bortezomib leads to painful neuropathy remains unclear. In the present study, we found that application of bortezomib significantly increased the expression of NOD-like receptor family pyrin domain containing 3 (NLRP3) and phosphorylated signal transducer and activator of transcription-3 (STAT3) in dorsal root ganglion (DRG). Intrathecal injection of NLRP3 siRNA significantly prevented the mechanical allodynia induced by bortezomib treatment, and intrathecal injection of recombinant adeno-associated virus vector encoding NLRP3 markedly decreased paw withdrawal threshold of naive rats. Furthermore, the expressions of p-STAT3 were colocalized with NLRP3positive cells in DRG neurons, and inhibition of STAT3 by intrathecal injection of AAV-Cre-GFP into STAT3(flox/flox) mice or inhibitor S3I-201 suppressed the upregulation of NLRP3 and mechanical allodynia induced by bortezomib treatment. Chromatin immunoprecipitation further found that bortezomib increased the recruitment of STAT3, as well as the acetylation of histone H3 and H4, in the NLRP3 promoter region in DRG neurons. Importantly, inhibition of the STAT3 activity by using S3I-201 or DRG local deficiency of STAT3 also significantly prevented the upregulated H3 and H4 acetylation in the NLRP3 promoter region following bortezomib treatment. Altogether, our results suggest that the upregulation of NLRP3 in DRG via STAT3-dependent histone acetylation is critically involved in bortezomib-induced mechanical allodynia.