Zhang Yonghui, Sang Rui, Bao Jingyin, Jiang Zhihao, Qian Danni, Zhou Yi, Su Wenfeng, Wei Jinhuan, Zhao Long, Wei Zhongya, Zhao Yayu, Shi Minxin, Chen Gang
Basic Medical Research Center, Medical School of Nantong University, Co-Innovation Center of Neuroregeneration, Nantong 226001, Jiangsu Province, China; Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong 226001, Jiangsu Province, China.
Basic Medical Research Center, Medical School of Nantong University, Co-Innovation Center of Neuroregeneration, Nantong 226001, Jiangsu Province, China.
Brain Behav Immun. 2023 Mar;109:308-320. doi: 10.1016/j.bbi.2023.02.004. Epub 2023 Feb 6.
Pain is one of the most severe complications affecting the quality of life of cancer patients. Although substantial progress has been made in the diagnosis and treatment of cancer, the neurobiological mechanism of cancer pain is still unclear. In the present study, we identified the critical role of CXC chemokine 2 (CXCL2), released by Schwann cells after being activated by cancer cells, in maintaining cancer-induced macrophage infiltration and the resulting mechanical hypersensitivity and persistent spontaneous nociception. In vitro, Schwann cells cocultured with breast cancer cells exhibited a significant increase in CXCL2 expression; in addition, conditioned medium from Schwann cells activated by breast cancer cells had a similar effect to recombinant CXCL2 in terms of inducing macrophage migration. Targeting CXCL2 signaling by both CXC chemokine receptor 2 (CXCR2) antagonist pharmacological blockade and anti-CXCL2 mAb immunological blockade robustly prevented conditioned medium-induced macrophage migration. In vivo, both application of recombinant CXCL2 and perineural breast cancer cell implantation resulted in mechanical hypersensitivity and persistent spontaneous nociception in mice, along with increased macrophage infiltration into the sciatic nerves. Similar to the in vitro results, inhibition of CXCL2/CXCR2 signaling or conditional knockdown of CXCL2 in sciatic nerve Schwann cells effectively attenuated breast cancer cell-induced mechanical hypersensitivity, persistent spontaneous nociception, and macrophage recruitment in the sciatic nerve. Mechanistically, we found that redox effector factor-1 (Ref-1) secreted by breast cancer cells activated hypoxia inducible factor-1α (HIF-1α) expression and inhibited reactive oxygen species (ROS) production in Schwann cells, ultimately inducing CXCL2 expression in Schwann cells. In brief, the present study expands new insights into cancer pain mechanisms from promising animal models to provide new strategies for the control of cancer pain.
疼痛是影响癌症患者生活质量的最严重并发症之一。尽管在癌症的诊断和治疗方面取得了重大进展，但癌症疼痛的神经生物学机制仍不清楚。在本研究中，我们确定了雪旺细胞在被癌细胞激活后释放的CXC趋化因子2（CXCL2）在维持癌症诱导的巨噬细胞浸润以及由此产生的机械性超敏反应和持续性自发伤害感受中的关键作用。在体外，与乳腺癌细胞共培养的雪旺细胞CXCL2表达显著增加；此外，乳腺癌细胞激活的雪旺细胞条件培养基在诱导巨噬细胞迁移方面与重组CXCL2具有相似的作用。通过CXC趋化因子受体2（CXCR2）拮抗剂药理阻断和抗CXCL2单克隆抗体免疫阻断靶向CXCL2信号通路，有力地阻止了条件培养基诱导的巨噬细胞迁移。在体内，重组CXCL2的应用和神经周围乳腺癌细胞植入均导致小鼠出现机械性超敏反应和持续性自发伤害感受，同时坐骨神经中的巨噬细胞浸润增加。与体外结果相似，抑制CXCL2/CXCR2信号通路或在坐骨神经雪旺细胞中条件性敲低CXCL2可有效减轻乳腺癌细胞诱导的机械性超敏反应、持续性自发伤害感受以及坐骨神经中的巨噬细胞募集。从机制上讲，我们发现乳腺癌细胞分泌的氧化还原效应因子-1（Ref-1）激活了雪旺细胞中缺氧诱导因子-1α（HIF-1α）的表达并抑制了活性氧（ROS）的产生，最终诱导雪旺细胞中CXCL2的表达。简而言之，本研究从有前景的动物模型扩展了对癌症疼痛机制的新见解，为控制癌症疼痛提供了新策略。
