Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain
Elizabeth A. Old, … , Mauro Perretti, Marzia Malcangio
Elizabeth A. Old, … , Mauro Perretti, Marzia Malcangio
Published April 17, 2014
Citation Information: J Clin Invest. 2014;124(5):2023-2036. https://doi.org/10.1172/JCI71389.
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Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain

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.

Authors

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

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Figure 6

FKN triggers ROS production in CX3CR1 macrophages — a role for TRPA1 in VCR-induced allodynia.

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FKN triggers ROS production in CX3CR1 macrophages — a role for TRPA1 in ...
(A–C) FKN induces ROS production in macrophages; antioxidant treatment attenuates VCR-induced allodynia. (A) Acetyl-l-carnitine (ALC; 200 mg/kg twice a day) attenuates development of VCR-induced allodynia. Data are expressed as 50% paw withdrawal thresholds measured 1 hour after VCR (mean ± SEM, n = 10 mice per group). ***P < 0.001 compared to control (VEH SAL), ###P < 0.001 compared to VCR (VEH VCR), 2-way RM ANOVA, post-hoc Holm-Sidak. (B and C) FKN (mouse recombinant FKN [mrFKN]) 200 ng/ml) treatment of biogel-elicited macrophages from WT or KO mice induced ROS production in WT cells only. Data normalized to PMA at each time point (mean ± SEM, cells from 4 mice per group). *P < 0.05, ***P < 0.001 compared to WT mice, 2-way ANOVA, Bonferroni post-hoc. (B and C) ROS generation, as measured by (B) bioluminescence following luminol (60 μm) incubation and by (C) fluorescence following DCFDA incubation (5 μM). (D and E) Trpa1 KO mice develop less severe VCR-induced allodynia than WT mice. (D) Data are expressed as 50% paw withdrawal thresholds (mean ± SEM, n = 7 mice per VCR groups; n = 6 per saline group). ***P < 0.001 compared to baseline thresholds, ###P < 0.001 compared to vehicle treated, †††P < 0.001 compared to WT VCR, 2-way RM ANOVA, post-hoc Holm-Sidak. (E) Allodynia index calculated as AUC from 0 to 24 days (ALL TIME); 0 to 4 days (First CYCLE); 7 to 11 days (Second CYCLE); 12 to 24 days (Recovery). Smaller area AUC represents greater allodynia (mean ± SEM, n = 7 mice per VCR groups, n = 6 mice per saline group). ###P < 0.001 compared to vehicle treated, †††P < 0.001 compared to WT VCR treatment, 1-way ANOVA, post-hoc Holm-Sidak.