Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan.
School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan.
Mol Neurobiol. 2024 Feb;61(2):707-724. doi: 10.1007/s12035-023-03582-7. Epub 2023 Sep 1.
The role of heat shock protein 27 (HSP27), a chaperone, in neuropathic pain after nerve injury has not been systematically surveyed despite its neuroprotective and regeneration-promoting effects. In this study, we found that HSP27 expression in sensory neurons of the dorsal root ganglia (DRG) mediated nerve injury-induced neuropathic pain. Neuropathic pain behaviors were alleviated by silencing HSP27 in the DRG of a rat spinal nerve ligation (SNL) model. Local injection of an HSP27-overexpression construct into the DRG of naïve rats elicited neuropathic pain behaviors. HSP27 interacted with a purinergic receptor, P2X3, and their expression patterns corroborated the induction and reversal of neuropathic pain according to two lines of evidence: colocalization immunohistochemically and immunoprecipitation biochemically. In a cell model cotransfected with HSP27 and P2X3, the degradation rate of P2X3 was reduced in the presence of HSP27. Such an alteration was mediated by reducing P2X3 ubiquitination in SNL rats and was reversed after silencing HSP27 in the DRGs of SNL rats. In summary, the interaction of HSP27 with P2X3 provides a new mechanism of injury-induced neuropathic pain that could serve as an alternative therapeutic target.
热休克蛋白 27（HSP27）作为伴侣蛋白，尽管具有神经保护和促进再生的作用，但在神经损伤后的神经病理性疼痛中其作用尚未被系统研究过。在这项研究中，我们发现背根神经节（DRG）感觉神经元中的 HSP27 表达介导了神经损伤引起的神经病理性疼痛。在大鼠脊神经结扎（SNL）模型中，沉默 DRG 中的 HSP27 可减轻神经病理性疼痛行为。将 HSP27 过表达构建体局部注射到未受伤的大鼠的 DRG 中会引起神经病理性疼痛行为。HSP27 与嘌呤能受体 P2X3 相互作用，其表达模式根据两条证据证实了诱导和逆转神经病理性疼痛：免疫组织化学上的共定位和免疫沉淀的生化分析。在共转染 HSP27 和 P2X3 的细胞模型中，HSP27 的存在降低了 P2X3 的降解率。这种改变是通过减少 SNL 大鼠中 P2X3 的泛素化介导的，并且在 SNL 大鼠的 DRG 中沉默 HSP27 后得到逆转。总之，HSP27 与 P2X3 的相互作用为损伤诱导的神经病理性疼痛提供了一种新的机制，可作为一种替代的治疗靶点。
