Department of Pain Management, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Respiratory, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China.
Int J Cancer. 2020 May 15;146(10):2810-2821. doi: 10.1002/ijc.32652. Epub 2019 Sep 14.
Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect of chemotherapeutics. The mechanisms of CIPN remain substantially unidentified, although inflammation-induced peripheral sensitization has been indicated as an important factor. Here, we aimed to illustrate the role of the matrix metalloproteinase (MMP)-9-related signaling pathway in the process of CIPN. Oxaliplatin (L-OHP) was administered to mice to establish the CIPN model. Gelatin zymography was used to measure MMP-9/2 activities. Western blotting and immunohistochemistry were used to measure the expression of high-mobility group box-1 (HMGB-1), calcitonin gene-related peptide and ionized calcium-binding adapter molecule 1. Mechanical withdrawal was measured by von Frey hairs testing. Raw 264.7 cells and SH-SY5Y cells were cultured to investigate cell signaling in vitro. Here, we report that L-OHP-induced mechanical pain in mice with significant MMP-9/2 activation in dorsal root ganglion (DRG) neurons. MMP-9 inhibition or knockout alleviated the occurrence of CIPN directly. MMP-9/2 were released from macrophages and neurons in the DRG via the HMGB-1-toll-like receptor 4 (TLR4)-phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) axis, because MMP-9/2 activities could be reduced by macrophage scavengers or PI3Kγ knockout in CIPN mice. The in vitro data revealed that induced MMP-9 activity by recombinant HMGB-1 could be abolished by TLR4, PI3K or Akt inhibitors. Finally, it was shown that N-acetyl-cysteine (NAC) could reduce MMP-9/2 activities and attenuate CIPN effectively and safely. The HMGB-1-TLR4-PI3K/Akt-MMP-9 axis is involved in the crosstalk between macrophages and neurons in the pathological process of CIPN in mice. Direct inhibition of MMP-9 by NAC may be a potential therapeutic regimen for CIPN treatment.
化疗诱导的周围神经病（CIPN）是化疗药物的一个显著副作用。尽管炎症诱导的外周敏化已被表明是一个重要因素，但 CIPN 的机制仍未完全确定。在这里，我们旨在阐明基质金属蛋白酶（MMP）-9 相关信号通路在 CIPN 过程中的作用。用奥沙利铂（L-OHP）给小鼠给药以建立 CIPN 模型。明胶酶谱法用于测量 MMP-9/2 活性。Western blot 和免疫组织化学用于测量高迁移率族框 1（HMGB-1）、降钙素基因相关肽和离子钙结合接头分子 1 的表达。通过 von Frey 毛发测试测量机械退缩。培养 Raw 264.7 细胞和 SH-SY5Y 细胞以研究体外细胞信号。在这里，我们报告 L-OHP 诱导的小鼠机械疼痛与背根神经节（DRG）神经元中明显的 MMP-9/2 激活有关。MMP-9 抑制或敲除直接减轻 CIPN 的发生。MMP-9/2 通过 HMGB-1- Toll 样受体 4（TLR4）-磷酸肌醇 3-激酶（PI3K）/蛋白激酶 B（Akt）轴从 DRG 中的巨噬细胞和神经元中释放，因为在 CIPN 小鼠中，巨噬细胞清除剂或 PI3Kγ 敲除可降低 MMP-9/2 活性。体外数据表明，重组 HMGB-1 诱导的 MMP-9 活性可被 TLR4、PI3K 或 Akt 抑制剂消除。最后，结果表明 N-乙酰半胱氨酸（NAC）可有效且安全地降低 MMP-9/2 活性并减轻 CIPN。HMGB-1-TLR4-PI3K/Akt-MMP-9 轴参与了 CIPN 小鼠中巨噬细胞和神经元之间的病理过程中的串扰。NAC 对 MMP-9 的直接抑制可能是治疗 CIPN 的一种潜在治疗方案。
