title: Dichotomy of CCL21 and CXCR3 in nerve injury-evoked and autoimmunity-evoked hyperalgesia.
abstract: 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.
authors: Pharmazentrum Frankfurt, Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
authors: Katja
authors: K
authors: Schmitz
authors: Geethanjali
authors: G
authors: Pickert
authors: Nina
authors: N
authors: Wijnvoord
authors: Annett
authors: A
authors: Häussler
authors: Irmgard
authors: I
authors: Tegeder
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D054421:Chemokine CCL21 / Q000235:genetics / Q000378:metabolism*; D003080:Cold Temperature; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006358:Hot Temperature; D006930:Hyperalgesia / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology; D009437:Neuralgia / Q000276:immunology / Q000378:metabolism; D010147:Pain Measurement; D060888:Real-Time Polymerase Chain Reaction; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000473:pathology; D013601:T-Lymphocytes / Q000502:physiology
chemical_list: D054421:Chemokine CCL21; D054367:Receptors, CXCR3