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Chemokines in neuron–glial cell interaction and pathogenesis of neuropathic pain

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Abstract

Neuropathic pain resulting from damage or dysfunction of the nervous system is a highly debilitating chronic pain state and is often resistant to currently available treatments. It has become clear that neuroinflammation, mainly mediated by proinflammatory cytokines and chemokines, plays an important role in the establishment and maintenance of neuropathic pain. Chemokines were originally identified as regulators of peripheral immune cell trafficking and were also expressed in neurons and glial cells in the central nervous system. In recent years, accumulating studies have revealed the expression, distribution and function of chemokines in the spinal cord under chronic pain conditions. In this review, we provide evidence showing that several chemokines are upregulated after peripheral nerve injury and contribute to the pathogenesis of neuropathic pain via different forms of neuron–glia interaction in the spinal cord. First, chemokine CX3CL1 is expressed in primary afferents and spinal neurons and induces microglial activation via its microglial receptor CX3CR1 (neuron-to-microglia signaling). Second, CCL2 and CXCL1 are expressed in spinal astrocytes and act on CCR2 and CXCR2 in spinal neurons to increase excitatory synaptic transmission (astrocyte-to-neuron signaling). Third, we recently identified that CXCL13 is highly upregulated in spinal neurons after spinal nerve ligation and induces spinal astrocyte activation via receptor CXCR5 (neuron-to-astrocyte signaling). Strategies that target chemokine-mediated neuron-glia interactions may lead to novel therapies for the treatment of neuropathic pain.

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Abbreviations

AD:

Alzheimer’s disease

AMPA:

Alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate

BCP:

Bone cancer pain

CCI:

Chronic constriction injury

CFA:

Complete Freund’s adjuvant

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

DRG:

Dorsal root ganglion

EAE:

Experimental autoimmune encephalomyelitis

ERK:

Extracellular signal-regulated kinase

EPSC:

Excitatory postsynaptic currents

GABA:

Gamma-aminobutyric acid

IL:

Interleukin

IAMNT:

Inferior alveolar nerve and mental nerve transection

JNK:

c-Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinase

MCP-1:

Monocytes chemoattractant protein-1

MS:

Multiple sclerosis

LTP:

Long-term potentiation

NMDA:

N-methyl-d-aspartic acid

pIONL:

Partial infraorbital nerve ligation

PNS:

Peripheral nervous system

pSNL:

Partial sciatic nerve ligation

SNL:

Spinal nerve ligation

SNI:

Spared nerve injury

TNF-α:

Tumor necrosis factor-alpha

TG:

Trigeminal ganglion

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Acknowledgements

This study was supported by the grants from the National Natural Science Foundation of China (NSFC 31371121, 81400915, 81571070, and 31671091), the National Science Foundation for Young Scientists of Jiangsu Province (BK20140427), the Qing Lan Project, and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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  1. Department of Human Anatomy, School of Medicine, Nantong University, Nantong, Jiangsu, 226001, China

    Zhi-Jun Zhang

  2. Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Neuroregeneration, Nantong, Jiangsu, 226001, China

    Zhi-Jun Zhang, Bao-Chun Jiang & Yong-Jing Gao

  3. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, 226001, China

    Yong-Jing Gao

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  1. Zhi-Jun Zhang
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Zhang, ZJ., Jiang, BC. & Gao, YJ. Chemokines in neuron–glial cell interaction and pathogenesis of neuropathic pain. Cell. Mol. Life Sci. 74, 3275–3291 (2017). https://doi.org/10.1007/s00018-017-2513-1

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