Interleukin-6 induces microglial CX3CR1 expression in the spinal cord after peripheral nerve injury through the activation of p38 MAPK.
Peripheral nerve injury leading to neuropathic pain induces the upregulation of interleukin (IL)-6 and microglial CX3CR1 expression, and activation of p38 mitogen-activated protein kinase (MAPK) in the spinal cord. Here, we investigated whether IL-6 regulates CX3CR1 expression through p38 MAPK activation in the spinal cord in rats with chronic constriction injury (CCI) of the sciatic nerve. Similar temporal changes in the expression of IL-6, phosphorylated p38 MAPK and CX3CR1 were observed following CCI. The increases in CX3CR1 expression, p38 MAPK activation and pain behavior after CCI were suppressed by blocking IL-6 action with a neutralizing antibody, while they were enhanced by supplying exogenous recombinant rat IL-6 (rrIL-6). rrIL-6 also induced increases in spinal CX3CR1 expression, p38 MAPK activation and pain behavior in naive rats without nerve injury. Furthermore, treatment with the p38 MAPK-specific inhibitor, SB203580, suppressed the increase in CX3CR1 expression induced by CCI or rrIL-6 treatment. Finally, blocking CX3CR1 or p38 MAPK activation prevented the development of mechanical allodynia and thermal hyperalgesia induced by CCI or rrIL-6 treatment. These results suggest a new mechanism of neuropathic pain, in which IL-6 induces microglial CX3CR1 expression in the spinal cord through p38 MAPK activation, enhancing the responsiveness of microglia to fractalkine in the spinal cord, thus playing an important role in neuropathic pain after peripheral nerve injury.
Lee
Kyung-Min
KM
Department of Anatomy, School of Medicine, Kyungpook National University, 2-101 Dongin-Dong, Daegu 700-422, South Korea.
Jeon
Sang-Min
SM
Cho
Hee-Jung
HJ
D000704:Analysis of Variance; D000818:Animals; D057134:Antibodies, Neutralizing; D015153:Blotting, Western; D000073883:CX3C Chemokine Receptor 1; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D017628:Microglia / Q000378:metabolism*; D009409:Nerve Crush; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019707:Receptors, Chemokine / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism*; D013127:Spinal Nerves / Q000293:injuries* / Q000378:metabolism; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D057134:Antibodies, Neutralizing; D000073883:CX3C Chemokine Receptor 1; C516305:CX3CR1 protein, rat; D015850:Interleukin-6; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D048051:p38 Mitogen-Activated Protein Kinases