2. Academic Validation
  3. Schwann cell-derived CXCL2 contributes to cancer pain by modulating macrophage infiltration in a mouse breast cancer model

Schwann cell-derived CXCL2 contributes to cancer pain by modulating macrophage infiltration in a mouse breast cancer model

  • Brain Behav Immun. 2023 Feb 6;S0889-1591(23)00029-6. doi: 10.1016/j.bbi.2023.02.004.
Yonghui Zhang 1,  Rui Sang 2,  Jingyin Bao 2,  Zhihao Jiang 2,  Danni Qian 2,  Yi Zhou 3,  Wenfeng Su 4,  Jinhuan Wei 2,  Long Zhao 2,  Zhongya Wei 4,  Yayu Zhao 4,  Minxin Shi 5,  Gang Chen 6
Affiliations

Affiliations

  • 1 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.
  • 2 Basic Medical Research Center, Medical School of Nantong University, Co-Innovation Center of Neuroregeneration, Nantong 226001, Jiangsu province, China.
  • 3 Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China.
  • 4 Key Laboratory of Neuroregeneration of Jiangsu and the Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, Jiangsu Province, China.
  • 5 Department of Thoracic Surgery, Tumor Hospital Affiliated to Nantong University, Nantong 226001, Jiangsu Province, China. Electronic address: 1017168199@qq.com.
  • 6 Basic Medical Research Center, Medical School of Nantong University, Co-Innovation Center of Neuroregeneration, Nantong 226001, Jiangsu province, China; Key Laboratory of Neuroregeneration of Jiangsu and the Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, Jiangsu Province, China; Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China. Electronic address: chengang6626@ntu.edu.cn.
PMID: 36754246 DOI: 10.1016/j.bbi.2023.02.004
Abstract

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.

Keywords

Breast cancer; CXCL2/CXCR2 signaling; Cancer pain; Macrophage; Schwann cell.

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