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A novel interaction between CXCRand CCRsignalling in monocytes constitutes an underlying mechanism for persistent vincristine-induced pain.

A novel interaction between CXCRand CCRsignalling in monocytes constitutes an underlying mechanism for persistent vincristine-induced pain.
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Montague K, Simeoli R, Valente J, Malcangio M,


Montague K, Simeoli R, Valente J, Malcangio M, (click to view)

Montague K, Simeoli R, Valente J, Malcangio M,

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Journal of neuroinflammation 2018 04 0615(1) 101 doi 10.1186/s12974-018-1116-6
Abstract
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, CXCRreceptor-mediated signalling in monocytes/macrophages in the sciatic nerve orchestrates the development of mechanical hypersensitivity (allodynia). CXCR-deficient mice however still develop allodynia, albeit delayed; thus, additional underlying mechanisms emerge as VCR accumulates. Whilst both patrolling and inflammatory monocytes express CXCR, only inflammatory monocytes express CCRreceptors. We therefore assessed the role of CCRin monocytes in later stages of VCR-induced allodynia.

METHODS
Mechanically evoked hypersensitivity was assessed in VCR-treated CCR- or CXCR-deficient mice. In CXCR-deficient mice, the CCRantagonist, 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 CXCR-deficient mice. In addition, THP-1 cells were used to assess CXCR-CCRreceptor interactions in vitro, with Western blot analysis and ELISA being used to assess expression of CCRand proinflammatory cytokines.

RESULTS
We show that CCRsignalling plays a mechanistic role in allodynia that develops in CXCR-deficient mice with increasing VCR exposure. Indeed, the CCRantagonist, RS-102895, proves ineffective in mice possessing functional CXCRreceptors but reduces VCR-induced allodynia in CXCR-deficient mice, in which CCRmonocytes are elevated by VCR. We suggest that a novel interaction between CXCRand CCRreceptors in monocytes accounts for the therapeutic effect of RS-102895 in CXCR-deficient mice. Indeed, we observe that CCR, along with its ligand, CCL, is elevated in the sciatic nerve in CXCR-deficient mice, whilst in THP-1 cells (human monocytes), downregulating CXCRupregulates CCRexpression via p38 MAP kinase signalling. We also show that the CXCR-CCRinteraction in vitro regulates the release of pronociceptive cytokines TNF-α and IL1β.

CONCLUSIONS
Our data suggests that CCL/CCRsignalling plays a crucial role in VCR-induced allodynia in CXCR-deficient mice, which arises as a result of an interaction between CXCRand CCRin monocytes.

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