E Sihan, Song Qingbiao, Zhang Zhaokun, Liang Yingxia
School of Anesthesiology, Shandong Second Medical University, Weifang, China.
School of Clinical Medicine, Shandong Second Medical University, Weifang, China.
Mol Pain. 2025 Jan-Dec;21:17448069251377861. doi: 10.1177/17448069251377861. Epub 2025 Aug 30.
Peripheral nerve injury activates microglia in the spinal, promoting microglial polarization and facilitating neuropathic pain progression. Necroptosis, a form of cell death, plays a crucial role in various neurological diseases and receptor-interacting protein kinases 3(RIPK3) a key molecular in the process. This study investigates to explore that RIPK3 regulates microglial polarization through the TLR4/MyD88 signaling pathway in neuropathic pain. By using a chronic constriction injury (CCI) model in mice, we found that peripheral nerve injury promoted M1 polarization and activated the TLR4/MyD88 pathway in spinal cord; in BV-2 microglia models, TNF-α/Z-VAD co-induction triggered M1 polarization through TLR4/MyD88 pathway, TLR4 antagonists suppressed these effects both in vivo and in vitro. Administration of GSK'872 (RIPK3 inhibitor) inhibited TLR4/MyD88 pathway, reduced microglial M1 polarization, promoted microglial M2 polarization and alleviated CCI-induced hyperalgesia. These findings suggest that necroptosis is a key cellular mechanism in peripheral injury-induced neuropathic pain and that RIPK3 regulates microglial polarization via the TLR4/MyD88 pathway, providing a new target for neuropathic pain treatment and clinical prevention.
周围神经损伤会激活脊髓中的小胶质细胞，促进小胶质细胞极化并加速神经性疼痛的发展。坏死性凋亡作为一种细胞死亡形式，在各种神经疾病中起着关键作用，而受体相互作用蛋白激酶3（RIPK3）是这一过程中的关键分子。本研究旨在探究RIPK3在神经性疼痛中是否通过Toll样受体4（TLR4）/髓样分化因子88（MyD88）信号通路调节小胶质细胞极化。通过建立小鼠慢性缩窄性损伤（CCI）模型，我们发现周围神经损伤促进了脊髓中小胶质细胞向M1型极化并激活了TLR4/MyD88信号通路；在BV-2小胶质细胞模型中，肿瘤坏死因子-α（TNF-α）/Z-VAD共同诱导通过TLR4/MyD88信号通路触发M1型极化，TLR4拮抗剂在体内和体外均抑制了这些效应。给予GSK'872（RIPK3抑制剂）可抑制TLR4/MyD88信号通路，减少小胶质细胞M1型极化，促进小胶质细胞M2型极化，并减轻CCI诱导的痛觉过敏。这些研究结果表明，坏死性凋亡是周围神经损伤诱导的神经性疼痛的关键细胞机制，且RIPK3通过TLR4/MyD88信号通路调节小胶质细胞极化，为神经性疼痛的治疗和临床预防提供了新靶点。
