SOCS3-Mediated Blockade of JAK/STAT3 Signaling Pathway Reveals Its Major Contribution to Spinal Cord Neuroinflammation and Mechanical Allodynia after Peripheral Nerve Injury

被引:170
作者
Dominguez, Elisa [1 ,3 ]
Mauborgne, Annie [1 ,3 ]
Mallet, Jacques [2 ,3 ]
Desclaux, Mathieu [2 ,3 ]
Pohl, Michel [1 ,3 ]
机构
[1] Univ Paris 06, INSERM, Ctr Rech, Pains Grp,Inst Cerveau & Moelle Epiniere,Unite Mi, F-75013 Paris, France
[2] INSERM, Ctr Rech, Biotechnol & Biotherapy Grp, Inst Cerveau & Moelle Epiniere,Unite Mixte Rech S, F-75013 Paris, France
[3] Univ Paris 06, F-75005 Paris, France
关键词
NEUROPATHIC PAIN DEVELOPMENT; ACTIVATED PROTEIN-KINASE; NEURONS; ASTROCYTES; RAT; ASTROGLIOSIS; REGULATOR; MICROGLIA; LIGATION; STAT3;
D O I
10.1523/JNEUROSCI.5007-09.2010
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:5754 / 5766
页数:13
相关论文
共 43 条
[1]   Chemokines, chemokine receptors and pain [J].
Abbadie, C .
TRENDS IN IMMUNOLOGY, 2005, 26 (10) :529-534
[2]   FURTHER EVIDENCE FOR PAIN-RELATED BEHAVIORS IN A MODEL OF UNILATERAL PERIPHERAL MONONEUROPATHY [J].
ATTAL, N ;
JAZAT, F ;
KAYSER, V ;
GUILBAUD, G .
PAIN, 1990, 41 (02) :235-251
[3]   A PERIPHERAL MONONEUROPATHY IN RAT THAT PRODUCES DISORDERS OF PAIN SENSATION LIKE THOSE SEEN IN MAN [J].
BENNETT, GJ ;
XIE, YK .
PAIN, 1988, 33 (01) :87-107
[4]   QUANTITATIVE ASSESSMENT OF TACTILE ALLODYNIA IN THE RAT PAW [J].
CHAPLAN, SR ;
BACH, FW ;
POGREL, JW ;
CHUNG, JM ;
YAKSH, TL .
JOURNAL OF NEUROSCIENCE METHODS, 1994, 53 (01) :55-63
[5]   EFFICIENT ANALYSIS OF EXPERIMENTAL-OBSERVATIONS [J].
DIXON, WJ .
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 1980, 20 :441-462
[6]   JAK/STAT3 pathway is activated in spinal cord microglia after peripheral nerve injury and contributes to neuropathic pain development in rat [J].
Dominguez, Elisa ;
Rivat, Cyril ;
Pommier, Blandine ;
Mauborgne, Annie ;
Pohl, Michel .
JOURNAL OF NEUROCHEMISTRY, 2008, 107 (01) :50-60
[7]   Detection of static and dynamic components of mechanical allodynia in rat models of neuropathic pain: are they signalled by distinct primary sensory neurones? [J].
Field, MJ ;
Bramwell, S ;
Hughes, J ;
Singh, L .
PAIN, 1999, 83 (02) :303-311
[8]   JNK-Induced MCP-1 Production in Spinal Cord Astrocytes Contributes to Central Sensitization and Neuropathic Pain [J].
Gao, Yong-Jing ;
Zhang, Ling ;
Samad, Omar Abdel ;
Suter, Marc R. ;
Yasuhiko, Kawasaki ;
Xu, Zhen-Zhong ;
Park, Jong-Yeon ;
Lind, Anne-Li ;
Ma, Qiufu ;
Ji, Ru-Rong .
JOURNAL OF NEUROSCIENCE, 2009, 29 (13) :4096-4108
[9]   Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4 [J].
Gilchrist, M ;
Thorsson, V ;
Li, B ;
Rust, AG ;
Korb, M ;
Kennedy, K ;
Hai, T ;
Bolouri, H ;
Aderem, A .
NATURE, 2006, 441 (7090) :173-178
[10]  
Goslin K., 1998, CULTURING NERVE CELL, P339