Dorsal Root Ganglion Infiltration by Macrophages Contributes to Paclitaxel Chemotherapy-Induced Peripheral Neuropathy.
Dorsal Root Ganglion Infiltration by Macrophages Contributes to Paclitaxel Chemotherapy-Induced Peripheral Neuropathy.
复制标题
DOI：
10.1016/j.jpain.2016.02.011
复制
发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
Dougherty PM
中科院分区：
文献类型：
--
作者：
Zhang H;Li Y;de Carvalho-Barbosa M;Kavelaars A;Heijnen CJ;Albrecht PJ;Dougherty PM
化疗诱导的周围神经病变(CIPN)是紫杉醇治疗癌症的破坏性和持续性副作用。最近的研究表明，紫杉醇可激活Toll样受体4(TLR4)信号通路，增加背根神经节细胞单核细胞趋化蛋白1(MCP-1)的表达。在这项研究中，我们试图确定该信号的一个重要结果，也是CIPN表型的关键步骤是否是巨噬细胞在背根神经节(DRG)中的募集和渗透。在这里，我们表明巨噬细胞的渗透确实发生在一个时间过程中，这一过程与Spraogue-Dawley大鼠的行为CIPN表型的开始相匹配。此外，全身性给予脂质体包裹的氯屈膦酸盐(阴离子小体)可部分逆转紫杉醇诱导的CIPN的行为体征，并减少背根节中肿瘤坏死因子α的表达。鞘内注射MCP-1中和抗体可减少紫杉醇诱导的巨噬细胞向背根节的募集，并阻断CIPN的行为体征。鞘内注射TLR4拮抗剂LPS-RS可阻断机械超敏反应，减少MCP-1的表达，阻断巨噬细胞向背根节的浸润。最后，在紫杉醇治疗后，克罗屈酮或脂多糖-RS抑制巨噬细胞向DRG的渗透，阻止了单独紫杉醇治疗后观察到的表皮内神经纤维(IENF)的丢失。综上所述，这些结果首次表明了一种机制联系，即紫杉醇激活TLR4导致DRG神经元MCP-1表达增加，导致巨噬细胞向表达炎症细胞因子的DRG渗透，这些事件的结合导致IENF丢失和CIPN行为体征的发展。
Chemotherapy-induced peripheral neuropathy (CIPN) is a disruptive and persistent side-effect of cancer treatment with paclitaxel. Recent reports showed that paclitaxel treatment results in the activation of Toll-like receptor 4 (TLR4) signaling and increased expression of monocyte chemotactic protein 1 (MCP-1) in dorsal root ganglion cells. In this study, we sought to determine whether an important consequence of this signaling and also a key step in the CIPN phenotype was the recruitment and infiltration of macrophages into dorsal root ganglia (DRG). Here, we show that macrophage infiltration does indeed occur in a time course that matches the onset of the behavioral CIPN phenotype in Sprague-Dawley rats. Moreover, depletion of macrophages by systemic administration of liposome-encapsulated clodronate (clophosome) partially reversed behavioral signs of paclitaxel-induced CIPN as well as reduced TNFα expression in DRG. Intrathecal injection of MCP-1 neutralizing antibodies reduced paclitaxel-induced macrophage recruitment into the DRG and also blocked the behavioral signs of CIPN. Intrathecal treatment with the TLR4 antagonist LPS-RS blocked mechanical hypersensitivity, reduced MCP-1 expression, and blocked the infiltration of macrophages into the DRG in paclitaxel treated rats. Finally, the inhibition of macrophage infiltration into DRG following paclitaxel treatment with clodronate or LPS-RS prevented the loss of intra-epidermal nerve fibers (IENFs) observed following paclitaxel treatment alone. Taken altogether, these results are the first to indicate a mechanistic link such that activation of TLR4 by paclitaxel leads to increased expression of MCP-1 by DRG neurons resulting in macrophage infiltration to the DRG that express inflammatory cytokines and the combination of these events results in IENF loss and the development of behavioral signs of CIPN.