CX3CL1-mediated macrophage activation contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy
CX3CL1-mediated macrophage activation contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy
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CX3CL1介导的巨噬细胞激活导致紫杉醇诱导的DRG神经元凋亡和疼痛性周围神经病变
DOI：
10.1016/j.bbi.2014.03.014
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发表时间：
2014-08-01
影响因子：
15.1
通讯作者：
Xin, Wen-Jun
中科院分区：
文献类型：
--
作者：
Huang, Zhen-Zhen;Li, Dai;Xin, Wen-Jun
疼痛性周围神经病变是紫杉醇治疗的一种剂量限制性副作用，它阻碍了癌症患者化疗的最佳临床管理。目前，其潜在机制在很大程度上仍然未知。在此，我们发现临床相关剂量的紫杉醇（3 x 8 mg/kg，累积剂量24 mg/kg）在体内和体外诱导A纤维初级感觉神经元中趋化因子CX 3CL 1的显著上调，以及巨噬细胞浸润到大鼠背根神经节（DRG）中。紫杉醇治疗还增加了裂解的caspase-3的表达，诱导初级传入终末纤维的丢失，并降低了脊髓背角坐骨神经诱发的A纤维反应，表明紫杉醇诱导的DRG神经元凋亡。此外，紫杉醇诱导的DRG神经元凋亡只发生在巨噬细胞存在的体外研究。鞘内或全身注射CX 3CL 1中和抗体阻断了紫杉醇诱导的DRG中巨噬细胞募集和神经元凋亡，并且还减弱了紫杉醇诱导的异常性疼痛。此外，通过全身施用氯膦酸盐来消耗巨噬细胞抑制紫杉醇诱导的异常性疼痛。阻断CX 3CL 1可降低巨噬细胞中p38 MAPK的活化，抑制p38 MAPK活性可阻断紫杉醇诱导的神经元凋亡和机械异常性疼痛的发生。这些发现提供了新的证据，CX 3CL 1募集的巨噬细胞有助于紫杉醇诱导的DRG神经元凋亡和疼痛性周围神经病变。(C)2014爱思唯尔公司All rights reserved.
Painful peripheral neuropathy is a dose-limiting side effect of paclitaxel therapy, which hampers the optimal clinical management of chemotherapy in cancer patients. Currently the underlying mechanisms remain largely unknown. Here we showed that the clinically relevant dose of paclitaxel (3 x 8 mg/kg, cumulative dose 24 mg/kg) induced significant upregulation of the chemokine CX3CL1 in the A-fiber primary sensory neurons in vivo and in vitro and infiltration of macrophages into the dorsal root ganglion (DRG) in rats. Paclitaxel treatment also increased cleaved caspase-3 expression, induced the loss of primary afferent terminal fibers and decreased sciatic-evoked A-fiber responses in the spinal dorsal horn, indicating DRG neuronal apoptosis induced by paclitaxel. In addition, the paclitaxel-induced DRG neuronal apoptosis occurred exclusively in the presence of macrophage in vitro study. Intrathecal or systemic injection of CX3CL1 neutralizing antibody blocked paclitaxel-induced macrophage recruitment and neuronal apoptosis in the DRG, and also attenuated paclitaxel-induced allodynia. Furthermore, depletion of macrophage by systemic administration of clodronate inhibited paclitaxel-induced allodynia. Blocking CX3CL1 decreased activation of p38 MAPK in the macrophage, and inhibition of p38 MAPK activity blocked the neuronal apoptosis and development of mechanical allodynia induced by paclitaxel. These findings provide novel evidence that CX3CL1-recruited macrophage contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy. (C) 2014 Elsevier Inc. All rights reserved.