Dichotomy of CCL21 and CXCR3 in nerve injury-evoked and autoimmunity-evoked hyperalgesia

Brain Behav Immun. 2013 Aug:32:186-200. doi: 10.1016/j.bbi.2013.04.011. Epub 2013 Apr 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Chemokine CCL21 / genetics
  • Chemokine CCL21 / metabolism*
  • Cold Temperature
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / metabolism*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Hot Temperature
  • Hyperalgesia / immunology*
  • Hyperalgesia / metabolism*
  • Hyperalgesia / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Microglia / physiology
  • Neuralgia / immunology
  • Neuralgia / metabolism
  • Pain Measurement
  • Real-Time Polymerase Chain Reaction
  • Receptors, CXCR3 / genetics
  • Receptors, CXCR3 / metabolism*
  • Spinal Cord / pathology
  • T-Lymphocytes / physiology


  • Chemokine CCL21
  • Receptors, CXCR3