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已经取得了实质性进展，但是癌症疼痛的神经生物学机制仍然不清楚。在本研究中，我们鉴定了CXCL2分泌的关键作用（由施万细胞在被癌细胞激活后释放），在维持癌症诱导的巨噬细胞浸润以及由此导致的机械性过敏和持续性自发性疼痛中发挥重要作用。在体外实验中，被乳腺癌细胞共培养的施万细胞表现出明显的CXCL2表达增加；此外，由乳腺癌细胞激活的施万细胞的调节培养基对诱导巨噬细胞迁移的作用类似于重组CXCL2。通过CXCR2拮抗剂药理阻断和抗CXCL2 mAb免疫阻断靶向CXCL2信号，可有效防止调节培养基诱导的巨噬细胞迁移。在体内，重组CXCL2的应用和腹神经埋入乳腺癌细胞均导致小鼠机械性过敏和持续性自发性疼痛，以及神经坐骨神经的巨噬细胞浸润增加。与体外结果类似，CXCL2 / CXCR2信号的抑制或梳状神经施万细胞中CXCL2的有条件敲除有效地减轻了乳腺癌细胞诱导的机械性过敏、持续性自发性疼痛和神经坐骨神经中的巨噬细胞招募。在机制上，我们发现，乳腺癌细胞分泌的还原氧化状态调节因子-1(Ref-1)激活缺氧诱导因子-1α(HIF-1α)表达，并抑制施万细胞中的反应性氧化物种(ROS)生成，最终诱导施万细胞中的CXCL2表达。总之，本研究从有前途的动物模型扩展了癌痛机制的新视角，为控制癌痛提供了新策略。版权所有©2023 Elsevier Inc.。保留所有权利。

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.Copyright © 2023 Elsevier Inc. All rights reserved.