The chemokine CCL21 is released from injured neurons and acts as a ligand of the chemokine receptor, CXCR3, which likely contributes to pro-inflammatory adaptations and secondary neuronal damage. CCL21-CXCR3 signalling may therefore impact on the development of neuropathic pain. By using the respective knockout mice we show that deficiency of CCL19/21 in plt/plt mice attenuates nerve injury evoked pain but not the hyperalgesia evoked by autoimmune encephalomyelitis (EAE). Oppositely, CXCR3-deficiency had no protective effect after traumatic nerve injury but reduced EAE-evoked hyperalgesia and was associated with reduced clinical EAE scores, a reduction of the pro-inflammatory cell infiltration and reduced upregulation of interferon gamma and interleukin-17 in the spinal cord. In contrast, microglia activation in the spinal cord after traumatic sciatic nerve injury was neither attenuated in CXCR3(-/-) nor plt/plt mice, nor in double knockouts. However, the severity of EAE, but not the hyperalgesia, was also reduced in plt/plt mice, which was associated with reduced infiltration of the spinal cord with CCR7+ T-cells, an increase of CD25+ T-cells and reduced upregulation of CXCL9 and 10, CCL11 and 12. The data show that CCL21 and CXCR3 have dichotomous functions in traumatic and EAE-evoked neuropathic pain suggesting diverse mechanisms likely requiring diverse treatments although both types of neuropathic pain are mediated in part through the immune activation.
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