Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA; Department of Physical Medicine and Rehabilitation, University of California, Irvine, CA, USA.
J Control Release. 2018 Nov 28;290:88-101. doi: 10.1016/j.jconrel.2018.10.003. Epub 2018 Oct 6.
Recently, many clinical trials have challenged the efficacy of current therapeutics for neuropathic pain after spinal cord injury (SCI) due to their life-threatening side-effects including addictions. Growing evidence suggests that persistent inflammatory responses after primary SCI lead to an imbalance between anti-inflammation and pro-inflammation, resulting in pathogenesis and maintenance of neuropathic pain. Conversely, a variety of data suggest that inflammation contributes to regeneration. Herein, we investigated long-term local immunomodulation using anti-inflammatory cytokine IL-10 or IL-4-encoding lentivirus delivered from multichannel bridges. Multichannel bridges provide guidance for axonal outgrowth and act as delivery vehicles. Anti-inflammatory cytokines were hypothesized to modulate the pro-nociceptive inflammatory niche and promote axonal regeneration, leading to neuropathic pain attenuation. Gene expression analyses demonstrated that IL-10 and IL-4 decreased pro-nociceptive genes expression versus control. Moreover, these factors resulted in an increased number of pro-regenerative macrophages and restoration of normal nociceptors expression pattern. Furthermore, the combination of bridges with anti-inflammatory cytokines significantly alleviated both mechanical and thermal hypersensitivity relative to control and promoted axonal regeneration. Collectively, these studies highlight that immunomodulatory strategies target multiple barriers to decrease secondary inflammation and attenuate neuropathic pain after SCI.
最近，许多临床试验由于其危及生命的副作用，包括成瘾，对脊髓损伤 (SCI) 后神经性疼痛的当前治疗方法的疗效提出了挑战。越来越多的证据表明，原发性 SCI 后的持续炎症反应导致抗炎和促炎之间的失衡，导致神经性疼痛的发病和维持。相反，各种数据表明炎症有助于再生。在此，我们通过多通道桥体递送抗炎细胞因子 IL-10 或 IL-4 编码慢病毒，研究了长期局部免疫调节。多通道桥体为轴突生长提供了指导，并充当了递药载体。抗炎细胞因子被假设可以调节促伤害性炎症小生境并促进轴突再生，从而减轻神经性疼痛。基因表达分析表明，与对照组相比，IL-10 和 IL-4 降低了促伤害性基因的表达。此外，这些因素导致促再生巨噬细胞数量增加，并恢复了正常的伤害感受器表达模式。此外，与对照组相比，桥体与抗炎细胞因子的组合可显著减轻机械和热敏感性，并促进轴突再生。总之，这些研究强调了免疫调节策略可以靶向多个障碍，以减少继发性炎症并减轻 SCI 后的神经性疼痛。
