Vascular Biology Center, Division of Hematology, Oncology & Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Department of Neurosurgery, University of California San Diego, La Jolla, California, USA.
Antioxid Redox Signal. 2021 Feb 1;34(4):279-293. doi: 10.1089/ars.2019.7913. Epub 2020 Aug 24.
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 (), 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. Spinal heme levels, TLR4 transcripts, oxidative stress, and ER stress were significantly higher in sickle mice than controls. , 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. 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. Heme-induced microglial activation TLR4 in the central nervous system contributes to the initiation and maintenance of sickle pain ER stress in SCD. . 34, 279-293.
终生疼痛是镰状细胞病（SCD）的一个显著特征。镰状细胞病理生物学如何引起疼痛尚不清楚。我们假设，由于持续的溶血导致细胞内游离血红素增加，激活了 Toll 样受体 4（TLR4），导致活性氧（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激活和神经炎症，最终导致急性和慢性疼痛。与对照组相比，镰状细胞小鼠的脊髓血红素水平、TLR4 转录本、氧化应激和 ER 应激显著升高。TLR4 在脊髓小胶质细胞中的抑制减弱了血红素诱导的 ROS 和 ER 应激。血红素处理导致镰状和对照小鼠的镰状疼痛特征（机械性和热痛觉过敏）呈时间依赖性增加；TLR4 敲除的镰状和对照小鼠则没有这种效应。在镰状细胞小鼠中敲除 TLR4 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 处理的镰状细胞小鼠；TLR4 的选择性小分子抑制剂（TAK242）显著减轻了慢性痛觉过敏，并具有更快的恢复速度和较轻的 H/R 诱发的急性疼痛。值得注意的是，用 salubrinal 减轻 ER 应激可改善镰状细胞小鼠的慢性痛觉过敏。我们的研究结果表明，游离血红素在急性和慢性镰状疼痛的发生中起因果作用，并表明 TLR4 和/或 ER 应激是治疗 SCD 疼痛的新的治疗靶点。血红素诱导的小胶质细胞激活 TLR4 在中枢神经系统中参与了镰状疼痛的起始和维持 SCD 中的 ER 应激。
