Reduced inflammatory and neuropathic pain and decreased spinal microglial response in fractalkine receptor (CX3CR1) knockout mice.
The chemokine fractalkine (FKN) is a critical mediator of spinal neuronal-microglial communication in chronic pain. Mature FKN is enzymatically cleaved from neuronal membranes and activation of its receptor, CX3CR1, which is expressed by microglia, induces phosphorylation of p38 MAPK. We used CX3CR1 knockout (KO) mice to examine pain behaviour in the absence of FKN signalling. Naive CX3CR1 KO mice had normal responses to acute noxious stimuli. However, KO mice showed deficits in inflammatory and neuropathic nociceptive responses. After intraplantar zymosan, KO mice did not display thermal hyperalgesia, whereas mechanical allodynia developed fully. In the partial sciatic nerve ligation model of neuropathic pain, both mechanical allodynia and thermal hyperalgesia were less severe in KO mice than in wild-types (WT). Dorsal horn Iba1 immunostaining and phosphorylation of p38 MAPK increased after injury in WT controls but not in KO animals. In WT mice, inflammation and nerve injury increased spinal cord CX3CR1 and FKN expression. FKN protein was also increased in KO mice following inflammation but not after neuropathy, suggesting the FKN/CX3CR1 system is differently affected in the two pain models. Loss of FKN/CX3CR1 neuroimmune communication attenuates hyperalgesia and allodynia in a modality-dependent fashion highlighting the complex nature of microglial response in pathological pain models.
Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
Amelia A
AA
Staniland
Anna K
AK
Clark
Rachel
R
Wodarski
Oscar
O
Sasso
Francesco
F
Maione
Fulvio
F
D'Acquisto
Marzia
M
Malcangio
D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054428:Chemokine CX3CL1 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006930:Hyperalgesia / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000378:metabolism / Q000503:physiopathology; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D020426:Sciatic Neuropathy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D013116:Spinal Cord / Q000378:metabolism* / Q000503:physiopathology; D015854:Up-Regulation / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C491049:Aif1 protein, mouse; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins; D054428:Chemokine CX3CL1; C471885:Cx3cr1 protein, mouse; D018836:Inflammation Mediators; D008840:Microfilament Proteins; D019707:Receptors, Chemokine; D048051:p38 Mitogen-Activated Protein Kinases