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A novel interaction between CX(3)CR(1) and CCR(2) signalling in monocytes constitutes an underlying mechanism for persistent vincristine-induced pain

BACKGROUND: A dose-limiting side effect of chemotherapeutic agents such as vincristine (VCR) is neuropathic pain, which is poorly managed at present. Chemokine-mediated immune cell/neuron communication in preclinical VCR-induced pain forms an intriguing basis for the development of analgesics. In a...

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Autores principales: Montague, Karli, Simeoli, Raffaele, Valente, Joao, Malcangio, Marzia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889528/
https://www.ncbi.nlm.nih.gov/pubmed/29625610
http://dx.doi.org/10.1186/s12974-018-1116-6
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author Montague, Karli
Simeoli, Raffaele
Valente, Joao
Malcangio, Marzia
author_facet Montague, Karli
Simeoli, Raffaele
Valente, Joao
Malcangio, Marzia
author_sort Montague, Karli
collection PubMed
description BACKGROUND: A dose-limiting side effect of chemotherapeutic agents such as vincristine (VCR) is neuropathic pain, which is poorly managed at present. Chemokine-mediated immune cell/neuron communication in preclinical VCR-induced pain forms an intriguing basis for the development of analgesics. In a murine VCR model, CX(3)CR(1) receptor-mediated signalling in monocytes/macrophages in the sciatic nerve orchestrates the development of mechanical hypersensitivity (allodynia). CX(3)CR(1)-deficient mice however still develop allodynia, albeit delayed; thus, additional underlying mechanisms emerge as VCR accumulates. Whilst both patrolling and inflammatory monocytes express CX(3)CR(1), only inflammatory monocytes express CCR(2) receptors. We therefore assessed the role of CCR(2) in monocytes in later stages of VCR-induced allodynia. METHODS: Mechanically evoked hypersensitivity was assessed in VCR-treated CCR(2)- or CX(3)CR(1)-deficient mice. In CX(3)CR(1)-deficient mice, the CCR(2) antagonist, RS-102895, was also administered. Immunohistochemistry and Western blot analysis were employed to determine monocyte/macrophage infiltration into the sciatic nerve as well as neuronal activation in lumbar DRG, whilst flow cytometry was used to characterise monocytes in CX(3)CR(1)-deficient mice. In addition, THP-1 cells were used to assess CX(3)CR(1)-CCR(2) receptor interactions in vitro, with Western blot analysis and ELISA being used to assess expression of CCR(2) and proinflammatory cytokines. RESULTS: We show that CCR(2) signalling plays a mechanistic role in allodynia that develops in CX(3)CR(1)-deficient mice with increasing VCR exposure. Indeed, the CCR(2) antagonist, RS-102895, proves ineffective in mice possessing functional CX(3)CR(1) receptors but reduces VCR-induced allodynia in CX(3)CR(1)-deficient mice, in which CCR(2)(+) monocytes are elevated by VCR. We suggest that a novel interaction between CX(3)CR(1) and CCR(2) receptors in monocytes accounts for the therapeutic effect of RS-102895 in CX(3)CR(1)-deficient mice. Indeed, we observe that CCR(2), along with its ligand, CCL(2), is elevated in the sciatic nerve in CX(3)CR(1)-deficient mice, whilst in THP-1 cells (human monocytes), downregulating CX(3)CR(1) upregulates CCR(2) expression via p38 MAP kinase signalling. We also show that the CX(3)CR(1)-CCR(2) interaction in vitro regulates the release of pronociceptive cytokines TNF-α and IL1β. CONCLUSIONS: Our data suggests that CCL(2)/CCR(2) signalling plays a crucial role in VCR-induced allodynia in CX(3)CR(1)-deficient mice, which arises as a result of an interaction between CX(3)CR(1) and CCR(2) in monocytes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-018-1116-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-58895282018-04-10 A novel interaction between CX(3)CR(1) and CCR(2) signalling in monocytes constitutes an underlying mechanism for persistent vincristine-induced pain Montague, Karli Simeoli, Raffaele Valente, Joao Malcangio, Marzia J Neuroinflammation Research BACKGROUND: A dose-limiting side effect of chemotherapeutic agents such as vincristine (VCR) is neuropathic pain, which is poorly managed at present. Chemokine-mediated immune cell/neuron communication in preclinical VCR-induced pain forms an intriguing basis for the development of analgesics. In a murine VCR model, CX(3)CR(1) receptor-mediated signalling in monocytes/macrophages in the sciatic nerve orchestrates the development of mechanical hypersensitivity (allodynia). CX(3)CR(1)-deficient mice however still develop allodynia, albeit delayed; thus, additional underlying mechanisms emerge as VCR accumulates. Whilst both patrolling and inflammatory monocytes express CX(3)CR(1), only inflammatory monocytes express CCR(2) receptors. We therefore assessed the role of CCR(2) in monocytes in later stages of VCR-induced allodynia. METHODS: Mechanically evoked hypersensitivity was assessed in VCR-treated CCR(2)- or CX(3)CR(1)-deficient mice. In CX(3)CR(1)-deficient mice, the CCR(2) antagonist, RS-102895, was also administered. Immunohistochemistry and Western blot analysis were employed to determine monocyte/macrophage infiltration into the sciatic nerve as well as neuronal activation in lumbar DRG, whilst flow cytometry was used to characterise monocytes in CX(3)CR(1)-deficient mice. In addition, THP-1 cells were used to assess CX(3)CR(1)-CCR(2) receptor interactions in vitro, with Western blot analysis and ELISA being used to assess expression of CCR(2) and proinflammatory cytokines. RESULTS: We show that CCR(2) signalling plays a mechanistic role in allodynia that develops in CX(3)CR(1)-deficient mice with increasing VCR exposure. Indeed, the CCR(2) antagonist, RS-102895, proves ineffective in mice possessing functional CX(3)CR(1) receptors but reduces VCR-induced allodynia in CX(3)CR(1)-deficient mice, in which CCR(2)(+) monocytes are elevated by VCR. We suggest that a novel interaction between CX(3)CR(1) and CCR(2) receptors in monocytes accounts for the therapeutic effect of RS-102895 in CX(3)CR(1)-deficient mice. Indeed, we observe that CCR(2), along with its ligand, CCL(2), is elevated in the sciatic nerve in CX(3)CR(1)-deficient mice, whilst in THP-1 cells (human monocytes), downregulating CX(3)CR(1) upregulates CCR(2) expression via p38 MAP kinase signalling. We also show that the CX(3)CR(1)-CCR(2) interaction in vitro regulates the release of pronociceptive cytokines TNF-α and IL1β. CONCLUSIONS: Our data suggests that CCL(2)/CCR(2) signalling plays a crucial role in VCR-induced allodynia in CX(3)CR(1)-deficient mice, which arises as a result of an interaction between CX(3)CR(1) and CCR(2) in monocytes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-018-1116-6) contains supplementary material, which is available to authorized users. BioMed Central 2018-04-06 /pmc/articles/PMC5889528/ /pubmed/29625610 http://dx.doi.org/10.1186/s12974-018-1116-6 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Montague, Karli
Simeoli, Raffaele
Valente, Joao
Malcangio, Marzia
A novel interaction between CX(3)CR(1) and CCR(2) signalling in monocytes constitutes an underlying mechanism for persistent vincristine-induced pain
title A novel interaction between CX(3)CR(1) and CCR(2) signalling in monocytes constitutes an underlying mechanism for persistent vincristine-induced pain
title_full A novel interaction between CX(3)CR(1) and CCR(2) signalling in monocytes constitutes an underlying mechanism for persistent vincristine-induced pain
title_fullStr A novel interaction between CX(3)CR(1) and CCR(2) signalling in monocytes constitutes an underlying mechanism for persistent vincristine-induced pain
title_full_unstemmed A novel interaction between CX(3)CR(1) and CCR(2) signalling in monocytes constitutes an underlying mechanism for persistent vincristine-induced pain
title_short A novel interaction between CX(3)CR(1) and CCR(2) signalling in monocytes constitutes an underlying mechanism for persistent vincristine-induced pain
title_sort novel interaction between cx(3)cr(1) and ccr(2) signalling in monocytes constitutes an underlying mechanism for persistent vincristine-induced pain
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889528/
https://www.ncbi.nlm.nih.gov/pubmed/29625610
http://dx.doi.org/10.1186/s12974-018-1116-6
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