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

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.

Elevation of the Chemokine Pair CXCL10/CXCR3 Initiates Sequential Glial Activation and Crosstalk During the Development of Bimodal Inflammatory Pain after Spinal Cord Ischemia Reperfusion

“…Because glial cells are the main effectors and regulators of the spinal cord, activated populations of glial cells could produce a wide variety of proinflammatory cytokines that strongly affect the pathogenesis of sensory hypersensitivity [6,8,17,22]. Among these cytokines, TNF-α and IL-6 are known to function as potent proinflammatory cytokines during the reperfusion period [6,27,28].…”

“…The sequential activation of and crosstalk between microglia and astrocytes is now known to be performed by soluble mediators, such as adenosine, growth factors, inflammatory chemokines and cytokines [3,8,9]. Among these mediators, chemokines are 8-14-kDa secreted proteins with conserved cysteine residues in their sequences.…”

Perturbations in neuroinflammatory pathways are associated with paclitaxel-induced peripheral neuropathy in breast cancer survivors

“…In fact, a growing body of preclinical evidence suggests that immune cells (e.g., macrophages, lymphocytes) and glial cells (e.g., Schwann cells) in the peripheral nervous system (PNS) and astrocytes and microglia in the central nervous system (CNS) play an important role in the induction and maintenance of neuropathic pain. (Krames, 2014;Zhang et al, 2017) This activation of the immune system results in the release of inflammatory mediators, within the DRG and dorsal horn, (Krames, 2014) that enhances neuronal excitability and results in pain hypersensitivity in peripheral neurons (Makker et al, 2017).…”

Koumine Decreases Astrocyte-Mediated Neuroinflammation and Enhances Autophagy, Contributing to Neuropathic Pain From Chronic Constriction Injury in Rats

“…Under some circumstances, such as peripheral nerve injury, tissue damage, and arthritis, spinal astrocytes rapidly transform to an activated state, which displays a closer correlation with chronic pain behaviors (Gao and Ji, 2010). Activated astrocytes can regulate the release of neurotrophic factors, inflammatory mediators, chemokines, adenosine and neurotransmitters, resulting in long-lasting thermal hyperalgesia and mechanical allodynia (Zhang et al, 2017). Although the pathogenesis of NP has not yet been fully elucidated, an inflammatory response caused by astrocyte activation is considered one of the most critical events.…”