Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain

Elizabeth A. Old, Suchita Nadkarni, John Grist, Clive Gentry, Stuart Bevan, Ki-Wook Kim, Adrian J. Mogg, Mauro Perretti, Marzia Malcangio*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

133 Citations (Scopus)

Abstract

A major dose-limiting side effect associated with cancer-treating antineoplastic drugs is the development of neuropathic pain, which is not readily relieved by available analgesics. A better understanding of the mechanisms that underlie pain generation has potential to provide targets for prophylactic management of chemotherapy pain. Here, we delineate a pathway for pain that is induced by the chemotherapeutic drug vincristine sulfate (VCR). In a murine model of chemotherapy-induced allodynia, VCR treatment induced upregulation of endothelial cell adhesion properties, resulting in the infiltration of circulating CX3CR1(+) monocytes into the sciatic nerve. At the endothelial-nerve interface, CX3CR1(+) monocytes were activated by the chemokine CX3CL1 (also known as fractalkine [FKN]), which promoted production of reactive oxygen species that in turn activated the receptor TRPA1 in sensory neurons and evoked the pain response. Furthermore, mice lacking CX3CR1 exhibited a delay in the development of allodynia following VCR administration. Together, our data suggest that CX3CR1 antagonists and inhibition of FKN proteolytic shedding, possibly by targeting ADAM10/17 and/or cathepsin S, have potential as peripheral approaches for the prophylactic treatment of chemotherapy-induced pain.

Original languageEnglish
Pages (from-to)2023-2036
Number of pages14
JournalJournal of Clinical Investigation
Volume124
Issue number5
Early online date17 Apr 2014
DOIs
Publication statusPublished - 31 May 2014

Keywords

  • FRACTALKINE RECEPTOR CX(3)CR1
  • DEFICIENCY PROTECTS MICE
  • PERIPHERAL NEUROPATHY
  • SENSORY NEURONS
  • MECHANICAL ALLODYNIA
  • COLD HYPERALGESIA
  • NERVOUS-SYSTEM
  • KNOCKOUT MICE
  • CATHEPSIN-S
  • PACLITAXEL

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