title: SOCS3-mediated blockade of JAK/STAT3 signaling pathway reveals its major contribution to spinal cord neuroinflammation and mechanical allodynia after peripheral nerve injury.
abstract: 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.
authors.affiliation: 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.
authors.forename: Elisa
authors.initials: E
authors.lastname: Dominguez
authors.forename: Annie
authors.initials: A
authors.lastname: Mauborgne
authors.forename: Jacques
authors.initials: J
authors.lastname: Mallet
authors.forename: Mathieu
authors.initials: M
authors.lastname: Desclaux
authors.forename: Michel
authors.initials: M
authors.lastname: Pohl
mesh_terms: 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*
chemical_list: 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
references.citation: J Neurosci. 2008 Aug 20;28(34):8489-501
references.pmid: 18716207
references.citation: J Neurosci. 2006 Mar 29;26(13):3551-60
references.pmid: 16571763
references.citation: J Neurosci. 2003 May 15;23(10):4017-22
references.pmid: 12764087
references.citation: Eur J Pain. 2010 Aug;14(7):682.e1-12
references.pmid: 19959384
references.citation: Cytokine. 2002 Jul 7;19(1):31-6
references.pmid: 12200111
references.citation: Eur J Pain. 2009 Mar;13(3):263-72
references.pmid: 18554968
references.citation: J Neurosci Methods. 1994 Jul;53(1):55-63
references.pmid: 7990513
references.citation: Pain. 1999 Nov;83(2):303-11
references.pmid: 10534603
references.citation: J Neurochem. 2006 Feb;96(4):1060-70
references.pmid: 16417589
references.citation: Nat Rev Neurosci. 2005 Jul;6(7):521-32
references.pmid: 15995723
references.citation: J Neurosci Methods. 2008 Jan 30;167(2):148-59
references.pmid: 17949823
references.citation: Nat Neurosci. 2007 Nov;10(11):1361-8
references.pmid: 17965656
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: J Neurosci. 2008 Jul 9;28(28):7231-43
references.pmid: 18614693
references.citation: J Biol Chem. 2004 May 7;279(19):19936-47
references.pmid: 14996842
references.citation: Pain. 1990 May;41(2):235-251
references.pmid: 2164179
references.citation: Diabetologia. 2008 Oct;51(10):1873-82
references.pmid: 18648765
references.citation: Neuron Glia Biol. 2007 Aug;3(3):255-68
references.pmid: 18504511
references.citation: Nature. 2006 May 11;441(7090):173-8
references.pmid: 16688168
references.citation: Immunity. 2008 Apr;28(4):477-87
references.pmid: 18400190
references.citation: J Clin Invest. 2009 Feb;119(2):295-304
references.pmid: 19139561
references.citation: Oncogene. 2007 Dec 6;26(55):7656-64
references.pmid: 17563747
references.citation: J Biol Chem. 2002 Oct 25;277(43):40594-601
references.pmid: 12191995
references.citation: J Neurosci. 2004 Nov 10;24(45):10211-22
references.pmid: 15537893
references.citation: J Neurosci Res. 2002 Feb 15;67(4):423-7
references.pmid: 11835308
references.citation: Trends Immunol. 2005 Oct;26(10):529-34
references.pmid: 16099720
references.citation: J Neurosci Res. 2004 Apr 15;76(2):265-76
references.pmid: 15048924
references.citation: J Neurochem. 2008 Oct;107(1):50-60
references.pmid: 18636982
references.citation: Nat Biotechnol. 2001 May;19(5):446-50
references.pmid: 11329014
references.citation: J Clin Invest. 2001 Dec;108(12):1781-8
references.pmid: 11748261
references.citation: Nat Rev Neurosci. 2009 Jan;10(1):23-36
references.pmid: 19096368
references.citation: Pain. 2005 Mar;114(1-2):149-59
references.pmid: 15733640
references.citation: J Biol Chem. 2006 Jun 9;281(23):15636-44
references.pmid: 16611639
references.citation: Nat Biotechnol. 1997 Sep;15(9):871-5
references.pmid: 9306402
references.citation: J Immunol. 1999 Jan 15;162(2):727-34
references.pmid: 9916692
references.citation: Annu Rev Pharmacol Toxicol. 1980;20:441-62
references.pmid: 7387124
references.citation: Pain. 1988 Apr;33(1):87-107
references.pmid: 2837713
references.citation: Eur J Pain. 2009 Sep;13(8):794-806
references.pmid: 18938092
references.citation: Nat Med. 2005 Aug;11(8):892-8
references.pmid: 16007096
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6493-8
references.pmid: 10829066
references.citation: Mol Ther. 2007 Apr;15(4):687-97
references.pmid: 17299402
references.citation: J Neurosci. 2009 Apr 1;29(13):4096-108
references.pmid: 19339605