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 4

Vincristine treatment induces infiltration of CX3CR1 monocyte-macrophages in the sciatic nerve.

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Vincristine treatment induces infiltration of CX3CR1 monocyte-macrophage...
(A and B) CX3CR1 monocyte-macrophages populate the sciatic nerve immediately after VCR treatment (day 1) and in the first cycle (days 0–4), but they are less numerous afterward (second cycle, days 7–11). (A) Representative photomicrographs showing CX3CR1-GFP+ cells (green) and F4/80+ cells (red) in sciatic nerve sections. Scale bar: 200 μm. (B) Positive cells were counted in 104 μm2 boxes (mean ± SEM, n = 4 mice per group). ***P < 0.001 compared to saline, ###P < 0.001 VCR day 1 compared to VCR day 11, 1-way ANOVA, post-hoc Tukey test. (C–E) Peritoneal monocyte-macrophages express Gr-1 marker (proinflammatory phenotype) following the first cycle of VCR (day 4). (C) Dot plot analysis of Gr-1+ and F4/80+ peritoneal cells analyzed by flow cytometry. (D) Cumulative data for relative percentage of Gr-1+ and Gr-1– cells in the F4/80+ population; mean ± SEM of 3 WT mice treated with vehicle or VCR. **P < 0.01, 1-way ANOVA followed by Tukey post-hoc test. (E) Cumulative data for relative percentage of Gr-1+ and Gr-1– cells in the GFP-positive population of Cx3cr1gfp/+ mice; mean ± SEM of 3 mice treated with vehicle or VCR. ***P < 0.001, 1-way ANOVA followed by Tukey post-hoc test.