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<p>Chronic pain is a prevalent and debilitating symptom in patients with nasopharyngeal carcinoma (NPC). Fresh insights indicate that tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) may undergo neuron-like differentiation, potentially contributing to pain mechanisms. By examining the <i>apolipoprotein E (APOE)</i> together with the <i>triggering receptor expressed on myeloid cells 2 (TREM2)</i>, this study aims to clarify their joint function in modulating differentiation and how this interplay might be implicated in chronic pain associated with NPC. Through comprehensive analysis using TCGA-NPC transcriptomic datasets and single-cell RNA sequencing (scRNA-seq), we assessed the molecular landscapes of both NPC-affected and healthy nasopharyngeal tissues. Differential gene expression and immune cell profiling identified macrophages as key players in the inflammatory response. Single-cell sequencing revealed a distinct subpopulation of neuron-like macrophages expressing neurogenesis-related genes. Macrophage-to-neuron-like cell transformation in response to NPC cells was examined through <i>in vitro</i> co-culture systems, highlighting the involvement of the APOE-TREM2 regulatory pathway. <i>In vivo</i> studies involved macrophage depletion and TREM2 knockdown in mouse models to evaluate the impact on chronic pain development. Infiltrating macrophages were significantly more abundant in NPC samples, with many exhibiting neuron-like features that were positively linked to high levels of <i>WNT5 A</i> expression. <i>In vitro</i>, NPC cells induced macrophage differentiation into neuron-like cells, a process regulated by <i>TREM2</i> and <i>APOE</i>. TREM2 knockdown in macrophages resulted in a reduction of chronic pain behaviors in mouse models, highlighting the contribution of the APOE-TREM2 Axis to NPC-associated chronic pain. Our findings demonstrate that NPC cells promote macrophage reprogramming through the APOE-TREM2 Axis, leading to neuron-like differentiation and contributing to chronic pain in NPC patients. Targeting this pathway may offer novel therapeutic strategies for managing chronic pain in NPC.</p> Graphical Abstract <p>1. Neuron-like macrophages contribute to chronic pain in nasopharyngeal carcinoma (NPC) through the APOE-TREM2 axis.</p> <p>2. Single-cell RNA sequencing reveals a unique subset of macrophages expressing neurogenesis-related genes in NPC tissues.</p> <p>3. APOE-TREM2 signaling regulates the neuronal-like differentiation of macrophages, promoting pain-related pathways in NPC.</p> <p>4. Targeting the APOE-TREM2 axis may offer novel therapeutic strategies for alleviating chronic pain in NPC patients.</p> <p></p>

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Neuron-like macrophage differentiation via the APOE-TREM2 axis contributes to chronic pain in nasopharyngeal carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月20日

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  • Hongxi Li,
  • Lanqing Zhao,
  • Jinwei Li,
  • Kailin Zhang,
  • Weiliang Bai,
  • Yu Chen

摘要

Chronic pain is a prevalent and debilitating symptom in patients with nasopharyngeal carcinoma (NPC). Fresh insights indicate that tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) may undergo neuron-like differentiation, potentially contributing to pain mechanisms. By examining the apolipoprotein E (APOE) together with the triggering receptor expressed on myeloid cells 2 (TREM2), this study aims to clarify their joint function in modulating differentiation and how this interplay might be implicated in chronic pain associated with NPC. Through comprehensive analysis using TCGA-NPC transcriptomic datasets and single-cell RNA sequencing (scRNA-seq), we assessed the molecular landscapes of both NPC-affected and healthy nasopharyngeal tissues. Differential gene expression and immune cell profiling identified macrophages as key players in the inflammatory response. Single-cell sequencing revealed a distinct subpopulation of neuron-like macrophages expressing neurogenesis-related genes. Macrophage-to-neuron-like cell transformation in response to NPC cells was examined through in vitro co-culture systems, highlighting the involvement of the APOE-TREM2 regulatory pathway. In vivo studies involved macrophage depletion and TREM2 knockdown in mouse models to evaluate the impact on chronic pain development. Infiltrating macrophages were significantly more abundant in NPC samples, with many exhibiting neuron-like features that were positively linked to high levels of WNT5 A expression. In vitro, NPC cells induced macrophage differentiation into neuron-like cells, a process regulated by TREM2 and APOE. TREM2 knockdown in macrophages resulted in a reduction of chronic pain behaviors in mouse models, highlighting the contribution of the APOE-TREM2 Axis to NPC-associated chronic pain. Our findings demonstrate that NPC cells promote macrophage reprogramming through the APOE-TREM2 Axis, leading to neuron-like differentiation and contributing to chronic pain in NPC patients. Targeting this pathway may offer novel therapeutic strategies for managing chronic pain in NPC.

Graphical Abstract

1. Neuron-like macrophages contribute to chronic pain in nasopharyngeal carcinoma (NPC) through the APOE-TREM2 axis.

2. Single-cell RNA sequencing reveals a unique subset of macrophages expressing neurogenesis-related genes in NPC tissues.

3. APOE-TREM2 signaling regulates the neuronal-like differentiation of macrophages, promoting pain-related pathways in NPC.

4. Targeting the APOE-TREM2 axis may offer novel therapeutic strategies for alleviating chronic pain in NPC patients.