TY - JOUR
T1 - Granulocyte-macrophage colony stimulating factor as an indirect mediator of nociceptor activation and pain
AU - Tewari, Damini
AU - Cook, Andrew D.
AU - Lee, Ming Chin
AU - Christensen, Anne D.
AU - Croxford, Andrew
AU - Becher, Burkhard
AU - Poole, Daniel
AU - Rajasekhar, Pradeep
AU - Bunnett, Nigel
AU - Smith, Julia E.
AU - Hamilton, John A.
AU - McMahon, Stephen B.
N1 - Funding Information:
Received Sept. 16, 2019; revised Jan. 7, 2020; accepted Jan. 14, 2020. Author contributions: D.T., A.D. Cook, J.E.S., J.A.H., and S.B.M. designed research; D.T., A.D. Cook, M.-C.L., A.D. Christensen,A.C.,B.B.,D.P.,P.R.,andN.B.performedresearch;D.T.analyzeddata;D.T.,A.D.Cook,J.A.H.,andS.B.M. wrote the paper. This work was supported by the Wellcome trust Senior Investigator Award to S.B.M., GlaxoSmith-Kline, and by Grant1043147fromtheNationalHealthandMedicalResearchCouncilofAustralia.WethankDr.FranziskaDenkfor advice on accessing publicly available RNA-seq data. Julia E. Smith is an employee of GSK. J.E.S. is an employee and shareholder of GSK. The remaining authors declare no competing financial interests. Correspondence should be addressed to Damini Tewari at damini.1.tewari@kcl.ac.uk. https://doi.org/10.1523/JNEUROSCI.2268-19.2020 Copyright © 2020 the authors
Funding Information:
This work was supported by the Wellcome trust Senior Investigator Award to S.B.M., GlaxoSmith-Kline, and by Grant 1043147 from the National Health and Medical Research Council of Australia. We thank Dr. Franziska Denk for advice on accessing publicly available RNA-seq data. Julia E. Smith is an employee of GSK.
Publisher Copyright:
Copyright © 2020 the authors.
PY - 2020/3/11
Y1 - 2020/3/11
N2 - 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.
AB - 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.
KW - Chronic pain
KW - GM-CSF
KW - Neuroimmune interaction
KW - Nerve Growth Factor/pharmacology
KW - Male
KW - STAT5 Transcription Factor/physiology
KW - Ganglia, Spinal/cytology
KW - Female
KW - Transcription, Genetic/drug effects
KW - Gene Expression Regulation/drug effects
KW - Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/drug effects
KW - Inflammation/chemically induced
KW - Mice, Inbred C57BL
KW - Cells, Cultured
KW - Cell Communication
KW - Chronic Pain/chemically induced
KW - Sensory Receptor Cells/drug effects
KW - MAP Kinase Signaling System/drug effects
KW - Granulocyte-Macrophage Colony-Stimulating Factor/physiology
KW - Macrophages/drug effects
KW - Animals
KW - Culture Media, Conditioned/pharmacology
KW - Calcium Signaling/drug effects
KW - Nociceptors/drug effects
KW - Mice
UR - http://www.scopus.com/inward/record.url?scp=85081751940&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85081751940&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.2268-19.2020
DO - 10.1523/JNEUROSCI.2268-19.2020
M3 - Article
C2 - 32019828
AN - SCOPUS:85081751940
SN - 0270-6474
VL - 40
SP - 2189
EP - 2199
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 11
ER -