Neuronal CC chemokines: the distinct roles of CCL21 and CCL2 in neuropathic pain

Abstract

The development of neuropathic pain in response to peripheral nerve lesion for a large part depends on microglia located at the dorsal horn of the spinal cord. Thus the injured nerve initiates a response of microglia, which represents the start of a cascade of events that leads to neuropathic pain development. For long it remained obscure how a nerve injury in the periphery would initiate a microglia response in the dorsal horn of the spinal cord. Recently, two chemokines have been suggested as potential factors that mediate the communication between injured neurons and microglia namely CCL2 and CCL21. This assumption is based on the following findings. Both chemokines are not found in healthy neurons, but are expressed in response to neuronal injury. In injured dorsal root ganglion cells CCL2 and CCL21 are expressed in vesicles in the soma and transported through the axons of the dorsal root into the dorsal horn of the spinal cord. Finally, microglia in vitro are known to respond to CCL2 and CCL21. Whereas the microglial chemokine receptor involved in CCL21-induced neuropathic pain is not yet defined the situation concerning the receptors for CCL2 in microglia in vivo is even less clear. Recent results obtained in transgenic animals clearly show that microglia in vivo do not express CCR2 but that peripheral myeloid cells and neurons do. This suggests that CCL2 expressed by injured dorsal root neurons does not act as neuron-microglia signal in contrast to CCL21. Instead, CCL2 in the injured dorsal root ganglia (DRG) may act as autocrine or paracrine signal and may stimulate first or second order neurons in the pain cascade and/or attract CCR2-expressing peripheral monocytes/macrophages to the spinal cord.

Increased local expressions of CX3CL1 and CCL2 are related to clinical severity in lumbar disk herniation patients with sciatic pain

“…CCL2 (C-C motif ligand 2), also known as monocytes chemoattractant protein-1, is a chemokine that has been demonstrated to play a critical role in chronic pain facilitation via CCR2. CCL2 and CX3CL1 signaling through CCR2 and CX3CR1 have been shown to be key factors in the recruitment of inflammation cells to tissue lesions or sites of inflammation,15 and so are key factors in persistence of neuropathic pain 16,17…”

An oral form of methylglyoxal-bis-guanylhydrazone reduces monocyte activation and traffic to the dorsal root ganglia in a primate model of HIV-peripheral neuropathy

“…The ligand for CCR2 is CCL2 or monocyte chemoattractant protein-1 (MCP-1) is elevated in SIV+ DRG 5 and most likely plays a role in recruiting inflammatory CCR2+ monocytes to the tissue. Additionally, CCR2-CCL2 interaction has been implicated in models of neuropathic pain 41,42 . It is unclear if CVC treatment will have a beneficial effect on PNS nerve pathologies.…”

Understanding Molecular Pathology along Injured Spinal Cord Axis: Moving Frontiers toward Effective Neuroprotection and Regeneration

“…Neurons are able to control microglia with two types of signals: "On" or "Off" [20]. Off signals (TGF-β, CD22, CX3CL1, neurotransmitters, and CD20) are found in healthy conditions to maintain homeostasis and also restrict microglial activities under inflammatory conditions to prevent damage to healthy tissue.…”