Heme Causes Pain in Sickle MiceviaToll-Like Receptor 4-Mediated Reactive Oxygen Species- and Endoplasmic Reticulum Stress-Induced Glial Activation
Heme Causes Pain in Sickle MiceviaToll-Like Receptor 4-Mediated Reactive Oxygen Species- and Endoplasmic Reticulum Stress-Induced Glial Activation
复制标题
血红素在Sickle MiceviaToll样受体4介导的活性氧和内质网应激诱导的神经胶质细胞激活中引起疼痛
DOI：
10.1089/ars.2019.7913
复制
发表时间：
2020-08-24
影响因子：
6.6
通讯作者：
Gupta, Kalpna
中科院分区：
文献类型：
--
作者：
Lei, Jianxun;Paul, Jinny;Gupta, Kalpna
目的：终身疼痛是镰状细胞病（SCD）的标志性特征。镰刀的病理生物学如何引起疼痛仍然是未知的。我们假设，由于持续的溶血而增加的无细胞血红素激活了Toll样受体4（TLR 4），导致活性氧簇（ROS）和内质网（ER）应激的形成。这些过程共同导致脊髓小胶质细胞活化和神经炎症，最终导致急性和慢性疼痛。结果：镰状小鼠脊髓血红素水平、TLR4转录水平、氧化应激和ER应激水平均显著高于对照组，在体外，抑制脊髓小胶质细胞中的TLR4可减轻血红素诱导的ROS和ER应激。血红素治疗导致镰刀疼痛的特征性特征（机械和热痛觉过敏）在镰刀和对照小鼠中的时间依赖性增加;这种作用在TLR4敲除镰刀和对照小鼠中不存在。TLR4缺失可减轻慢性和缺氧/复氧（H/R）诱发的急性痛觉过敏。用TLR4抑制剂resatorvid治疗的镰状小鼠;选择性TLR4小分子抑制剂（TAK242）显著降低了慢性痛觉过敏，并且具有较轻的H/R诱发的急性疼痛，恢复更快。值得注意的是，用salubrinal减少ER应激改善了镰状小鼠的慢性痛觉过敏。创新：我们的研究结果证明了游离血红素在急性和慢性镰状疼痛发生中的因果作用，并表明TLR4和/或ER应激是治疗SCD疼痛的新治疗靶点。结论：血红素通过TLR4激活中枢神经系统小胶质细胞，通过ER应激参与SCD镰状痛的发生和维持。
Aims:Lifelong pain is a hallmark feature of sickle cell disease (SCD). How sickle pathobiology evokes pain remains unknown. We hypothesize that increased cell-free heme due to ongoing hemolysis activates toll-like receptor 4 (TLR4), leading to the formation of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. Together, these processes lead to spinal microglial activation and neuroinflammation, culminating in acute and chronic pain. Results:Spinal heme levels, TLR4 transcripts, oxidative stress, and ER stress were significantly higher in sickle mice than controls.In vitro, TLR4 inhibition in spinal cord microglial cells attenuated heme-induced ROS and ER stress. Heme treatment led to a time-dependent increase in the characteristic features of sickle pain (mechanical and thermal hyperalgesia) in both sickle and control mice; this effect was absent in TLR4-knockout sickle and control mice. TLR4 deletion in sickle mice attenuated chronic and hypoxia/reoxygenation (H/R)-evoked acute hyperalgesia. Sickle mice treated with the TLR4 inhibitor resatorvid; selective small-molecule inhibitor of TLR4 (TAK242) had significantly reduced chronic hyperalgesia and had less severe H/R-evoked acute pain with quicker recovery. Notably, reducing ER stress with salubrinal ameliorated chronic hyperalgesia in sickle mice. Innovation:Our findings demonstrate the causal role of free heme in the genesis of acute and chronic sickle pain and suggest that TLR4 and/or ER stress are novel therapeutic targets for treating pain in SCD. Conclusion:Heme-induced microglial activationviaTLR4 in the central nervous system contributes to the initiation and maintenance of sickle painviaER stress in SCD.