Peripheral Nerve Resident Macrophages and Schwann Cells Mediate Cancer-Induced Pain

Francesco de Logu, Matilde Marini, Lorenzo Landini, Daniel Souza Monteiro de Araujo, Niccolo Bartalucci, Gabriela Trevisan, Gennaro Bruno, Martina Marangoni, Brian L. Schmidt, Nigel W. Bunnett, Pierangelo Geppetti, Romina Nassini

Research output: Contribution to journalArticlepeer-review


Although macrophages (MΦ) are known to play a central role in neuropathic pain, their contribution to cancer pain has not been established. Here we report that depletion of sciatic nerve resident MΦs (rMΦ) in mice attenuates mechanical/cold hypersensitivity and spontaneous pain evoked by intraplantar injection of melanoma or lung carcinoma cells. MΦ-colony stimulating factor (M-CSF) was upregulated in the sciatic nerve trunk and mediated cancer-evoked pain via rMΦ expansion, transient receptor potential ankyrin 1 (TRPA1) activation, and oxidative stress. Targeted deletion of Trpa1 revealed a key role for Schwann cell TRPA1 in sciatic nerve rMΦ expansion and pain-like behaviors. Depletion of rMΦs in a medial portion of the sciatic nerve prevented pain-like behaviors. Collectively, we identified a feed-forward pathway involving M-CSF, rMΦ, oxidative stress, and Schwann cell TRPA1 that operates throughout the nerve trunk to signal cancer-evoked pain. SIGNIFICANCE: Schwann cell TRPA1 sustains cancer pain through release of M-CSF and oxidative stress, which promote the expansion and the proalgesic actions of intraneural macrophages. GRAPHICAL ABSTRACT:

Original languageEnglish (US)
Pages (from-to)3387-3401
Number of pages15
JournalCancer Research
Issue number12
StatePublished - Jun 2021


  • Animals
  • Cancer Pain/etiology
  • Female
  • Hyperalgesia/etiology
  • Lung Neoplasms/complications
  • Macrophages/immunology
  • Male
  • Melanoma, Experimental/complications
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peripheral Nerves/immunology
  • Schwann Cells/immunology
  • TRPA1 Cation Channel/physiology

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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