JAK/STAT3 pathway is activated in spinal cord microglia after peripheral nerve injury and contributes to neuropathic pain development in rat.
Peripheral nerve lesion leads to the production of interleukin 6 (IL-6)-related neuropoietic cytokines involved in nerve protection and regeneration. This family of cytokines mainly signal through the signal transducer and activator of transcription (STAT) pathway that is locally activated in injured nerves. IL-6 is also involved in pain that frequently arises from peripheral nerve lesion. We investigated the possible activation of this major IL-6 signaling system in the spinal cord after peripheral nerve injury and its role in neuropathic pain. Ligation of L5-L6 spinal nerves (SNL) evoked an accumulation of active, phosphorylated form of STAT3 in microglial cells of dorsal spinal cord mostly in projection areas of injured nerves. SNL resulted also in a massive induction of IL-6 mRNA expression in dorsal root ganglia and increased concentration of IL-6 in dorsal spinal cord. Intrathecal injection of anti-rat IL-6 antibodies prevented the SNL-induced accumulation of phospho-STAT3 in the spinal cord. STAT3 pathway blockade with Janus kinase 2 inhibitor AG490 attenuated both mechanical allodynia and thermal hyperalgesia in SNL rats. These data show that in response to SNL injury Janus kinase/STAT3 system is activated mainly through IL-6 signaling in spinal microglia and that this transduction pathway participates in development of pain associated with nerve alteration.
Dominguez
Elisa
E
INSERM, UMR S 713, Paris, France.
Rivat
Cyril
C
Pommier
Blandine
B
Mauborgne
Annie
A
Pohl
Michel
M
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D006930:Hyperalgesia / Q000201:enzymology / Q000503:physiopathology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008026:Ligation; D008297:Male; D017628:Microglia / Q000201:enzymology / Q000378:metabolism*; D010525:Peripheral Nerves / Q000201:enzymology / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013116:Spinal Cord / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D013127:Spinal Nerves / Q000293:injuries / Q000503:physiopathology / Q000601:surgery; D015854:Up-Regulation / Q000502:physiology
D000906:Antibodies; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; C507927:Jak2 protein, rat; D053613:Janus Kinase 1; D053614:Janus Kinase 2