SOCS3-mediated blockade of JAK/STAT3 signaling pathway reveals its major contribution to spinal cord neuroinflammation and mechanical allodynia after peripheral nerve injury.
Neuropathic pain after peripheral nerve injury, associated with local neuroinflammation in the spinal cord, is a severe incapacitating condition with which clinical treatment remains challenging. Inflammatory molecules signal through various intracellular transduction pathways, activation of which may amplify and cause spreading of the inflammatory response. We showed recently that spinal nerve lesion leads to rapid activation of Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signal transduction pathway in dorsal spinal cord microglia in relation with enhanced levels of spinal interleukin-6 (IL-6) protein. Here, we selectively inactivated JAK/STAT3 signaling in rat dorsal spinal cord glia through local, lentiviral-mediated production of the suppressor of cytokine signaling SOCS3, a physiologic inhibitory protein of JAK/STAT3, and analyzed its consequences in a preclinical model of neuropathic pain. The targeted blockade of JAK/STAT3 activity prevented the abnormal expression of IL-6, CC chemokine ligand CCL2, and activating transcription factor ATF3 induced in the spinal cord by chronic constriction injury of the sciatic nerve (CCI) and substantially attenuated mechanical hypersensitivity (allodynia) in rats. In naive rats, intrathecal administration of a proalgesic cytokine IL-6 rapidly activated microglial JAK/STAT3 and induced downstream changes closely resembling CCI-evoked alterations. We identified downstream mechanisms through which JAK/STAT3 pathway activation leads to the spreading of neuroinflammation. Our findings reveal that JAK/STAT3 signaling plays a major role in spinal cord plasticity and mechanical allodynia associated with peripheral nerve injury.
Dominguez
Elisa
E
Pains Group and Biotechnology and Biotherapy Group, Centre de Recherches de l'Institut du Cerveau et de la Moelle Epinière, Inserm, Unité Mixte de Recherche en Santé 975, F-75013 Paris, France.
Mauborgne
Annie
A
Mallet
Jacques
J
Desclaux
Mathieu
M
Pohl
Michel
M
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000502:physiology; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D008392:Marmota; D010146:Pain / Q000209:etiology / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D010812:Physical Stimulation / Q000379:methods; D051381:Rats; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D020426:Sciatic Neuropathy / Q000150:complications / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology*
D018836:Inflammation Mediators; D050796:STAT3 Transcription Factor; C491410:Socs3 protein, rat; C494088:Stat3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053612:Janus Kinases
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