Cell-specific role of histone deacetylase 6 in chemotherapy-induced mechanical allodynia and loss of intraepidermal nerve fibers
Cell-specific role of histone deacetylase 6 in chemotherapy-induced mechanical allodynia and loss of intraepidermal nerve fibers
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DOI：
10.1097/j.pain.0000000000001667
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发表时间：
2019-12-01
期刊：
影响因子：
7.4
通讯作者：
Kavelaars, Annemieke
中科院分区：
文献类型：
--
作者：
Ma, Jiacheng;Trinh, Ronnie T.;Kavelaars, Annemieke
化疗引起的周围神经病变（CIPN）是癌症治疗的一种严重不良副作用，没有食品和药物管理局批准的预防或管理药物。使用背根神经节（DRG）的RNA测序分析，我们确定关键的贡献组蛋白脱乙酰酶6（HDAC 6）和线粒体损伤的顺铂诱导的神经病变的小鼠模型中的CIPN的建立。我们表明，使用ACV-1215或HDAC 6的整体缺失的HDAC 6的药理学抑制足以防止顺铂诱导的机械性异常性疼痛，表皮内神经纤维（IENF）的损失，以及在DRG神经元和周围神经的线粒体生物能缺陷的雄性和雌性小鼠。DRG中神经元细胞体中的生物能缺陷的特征在于氧化磷酸化减少，而神经中的线粒体缺陷是由于轴突线粒体含量减少。值得注意的是，在感觉神经元中删除HDAC 6可以防止顺铂诱导的IENF损失以及外周神经中线粒体生物能学和含量的减少。相比之下，感觉神经元中HDAC 6的缺失仅部分和短暂地防止顺铂诱导的机械异常性疼痛，并且不能防止DRG神经元中线粒体功能的损伤。我们进一步揭示了T细胞在HDAC 6抑制对CIPN的这些体征的保护作用中的关键作用。总之，我们发现顺铂诱导的机械性异常性疼痛与DRG神经元的线粒体损伤有关，而IENF的丢失与周围神经的生物能缺陷有关。此外，我们的研究结果确定了HDAC 6对机械异常性疼痛和IENF丢失的细胞特异性贡献，这些都是顺铂诱导的周围神经病变的特征。
Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse side effect of cancer treatment with no Food and Drug Administration-approved medication for its prevention or management. Using RNA sequencing analysis of dorsal root ganglia (DRG), we identify critical contributions of histone deacetylase 6 (HDAC6) and mitochondrial damage to the establishment of CIPN in a mouse model of cisplatin-induced neuropathy. We show that pharmacological inhibition of HDAC6 using ACV-1215 or global deletion of HDAC6 is sufficient to prevent cisplatin-induced mechanical allodynia, loss of intraepidermal nerve fibers (IENFs), and mitochondrial bioenergetic deficits in DRG neurons and peripheral nerves in male and female mice. The bioenergetic deficits in the neuronal cell bodies in the DRG are characterized by reduced oxidative phosphorylation, whereas the mitochondrial deficits in the nerves are due to a reduction in axonal mitochondrial content. Notably, deleting HDAC6 in sensory neurons protects against the cisplatin-induced loss of IENFs and the reduction in mitochondrial bioenergetics and content in the peripheral nerve. By contrast, deletion of HDAC6 in sensory neurons only partially and transiently prevents cisplatin-induced mechanical allodynia and does not protect against impairment of mitochondrial function in DRG neurons. We further reveal a critical role of T cells in the protective effects of HDAC6 inhibition on these signs of CIPN. In summary, we show that cisplatin-induced mechanical allodynia is associated with mitochondrial damage in DRG neurons, whereas the loss of IENFs is related to bioenergetic deficits in peripheral nerves. Moreover, our findings identify cell-specific contributions of HDAC6 to mechanical allodynia and loss of IENFs that characterize cisplatin-induced peripheral neuropathy.