Granulocyte-macrophage colony stimulating factor as an indirect mediator of nociceptor activation and pain

Damini Tewari, Andrew D. Cook, Ming Chin Lee, Anne D. Christensen, Andrew Croxford, Burkhard Becher, Daniel Poole, Pradeep Rajasekhar, Nigel Bunnett, Julia E. Smith, John A. Hamilton, Stephen B. McMahon

Research output: Contribution to journalArticlepeer-review


The interaction between the immune system and the nervous system has been at the center of multiple research studies in recent years. Whereas the role played by cytokines as neuronal mediators is no longer contested, the mechanisms by which cytokines modulate pain processing remain to be elucidated. In this study, we have analyzed the involvement of granulocyte-macrophage colony stimulating factor (GM-CSF) in nociceptor activation in male and female mice. Previous studies have suggested GM-CSF might directly activate neurons. However, here we established the absence of a functional GM-CSF receptor in murine nociceptors, and suggest an indirect mechanism of action, via immune cells. We report that GM-CSF applied directly to magnetically purified nociceptors does not induce any transcriptional changes in nociceptive genes. In contrast, conditioned medium from GM-CSF-treated murine macrophages was able to drive nociceptor transcription. We also found that conditioned medium from nociceptors treated with the well established pain mediator, nerve growth factor, could also modify macrophage gene transcription, providing further evidence for a bidirectional crosstalk. SIGNIFICANCE STATEMENT The interaction of the immune system and the nervous system is known to play an important role in the development and maintenance of chronic pain disorders. Elucidating the mechanisms of these interactions is an important step toward understanding, and therefore treating, chronic pain disorders. This study provides evidence for a two-way crosstalk between macrophages and nociceptors in the peripheral nervous system, which may contribute to the sensitization of nociceptors by cytokines in pain development.

Original languageEnglish (US)
Pages (from-to)2189-2199
Number of pages11
JournalJournal of Neuroscience
Issue number11
StatePublished - Mar 11 2020


  • Chronic pain
  • GM-CSF
  • Neuroimmune interaction
  • Nerve Growth Factor/pharmacology
  • Male
  • STAT5 Transcription Factor/physiology
  • Ganglia, Spinal/cytology
  • Female
  • Transcription, Genetic/drug effects
  • Gene Expression Regulation/drug effects
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/drug effects
  • Inflammation/chemically induced
  • Mice, Inbred C57BL
  • Cells, Cultured
  • Cell Communication
  • Chronic Pain/chemically induced
  • Sensory Receptor Cells/drug effects
  • MAP Kinase Signaling System/drug effects
  • Granulocyte-Macrophage Colony-Stimulating Factor/physiology
  • Macrophages/drug effects
  • Animals
  • Culture Media, Conditioned/pharmacology
  • Calcium Signaling/drug effects
  • Nociceptors/drug effects
  • Mice

ASJC Scopus subject areas

  • General Neuroscience


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