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:167
|
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
来源
JOURNAL OF NEUROSCIENCE | 2010年 / 30卷 / 16期
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 50 条
  • [1] SPTBN1 suppresses the progression of epithelial ovarian cancer via SOCS3-mediated blockade of the JAK/STAT3 signaling pathway
    Chen, Mo
    Zeng, Jia
    Chen, Shuyi
    Li, Jiajia
    Wu, Huijie
    Dong, Xuhui
    Lei, Yuan
    Zhi, Xiuling
    Yao, Liangqing
    AGING-US, 2020, 12 (11): : 10896 - 10911
  • [2] SOCS3-Mediated Blockade Reveals Major Contribution of JAK2/STAT5 Signaling Pathway to Lactation and Proliferation of Dairy Cow Mammary Epithelial Cells in Vitro
    Huang, Yu-Ling
    Zhao, Feng
    Luo, Chao-Chao
    Zhang, Xia
    Si, Yu
    Sun, Zhe
    Zhang, Li
    Li, Qing-Zhang
    Gao, Xue-Jun
    MOLECULES, 2013, 18 (10): : 12987 - 13002
  • [3] JAK/STAT3 pathway is activated in spinal cord microglia after peripheral nerve injury and contributes to neuropathic pain development in rat
    Dominguez, Elisa
    Rivat, Cyril
    Pommier, Blandine
    Mauborgne, Annie
    Pohl, Michel
    JOURNAL OF NEUROCHEMISTRY, 2008, 107 (01) : 50 - 60
  • [4] Alpinetin inhibits neuroinflammation and neuronal apoptosis via targeting the JAK2/STAT3 signaling pathway in spinal cord injury
    Xiao, Shining
    Zhang, Yu
    Liu, Zihao
    Li, Anan
    Tong, Weilai
    Xiong, Xu
    Nie, Jiangbo
    Zhong, Nanshan
    Zhu, Guoqing
    Liu, Jiaming
    Liu, Zhili
    CNS NEUROSCIENCE & THERAPEUTICS, 2023, 29 (04) : 1094 - 1108
  • [5] EYA2 suppresses the progression of hepatocellular carcinoma via SOCS3-mediated blockade of JAK/STAT signaling
    Liu, Ze-Kun
    Li, Can
    Zhang, Ren-Yu
    Wei, Ding
    Shang, Yu-Kui
    Yong, Yu-Le
    Kong, Ling-Min
    Zheng, Nai-Shan
    Liu, Ke
    Lu, Meng
    Liu, Man
    Hu, Cai-Xia
    Yang, Xiao-Zhen
    Chen, Zhi-Nan
    Bian, Huijie
    MOLECULAR CANCER, 2021, 20 (01)
  • [6] EYA2 suppresses the progression of hepatocellular carcinoma via SOCS3-mediated blockade of JAK/STAT signaling
    Ze-Kun Liu
    Can Li
    Ren-Yu Zhang
    Ding Wei
    Yu-Kui Shang
    Yu-Le Yong
    Ling-Min Kong
    Nai-Shan Zheng
    Ke Liu
    Meng Lu
    Man Liu
    Cai-Xia Hu
    Xiao-Zhen Yang
    Zhi-Nan Chen
    Huijie Bian
    Molecular Cancer, 20
  • [7] Mitochondrial STAT3 is negatively regulated by SOCS3 and upregulated after spinal cord injury
    Park, Keun Woo
    Lin, Ching-Yi
    Benveniste, Etty N.
    Lee, Yu-Shang
    EXPERIMENTAL NEUROLOGY, 2016, 284 : 98 - 105
  • [8] Argatroban promotes recovery of spinal cord injury by inhibiting the PAR1/JAK2/STAT3 signaling pathway
    Chenxi Zhao
    Tiangang Zhou
    Ming Li
    Jie Liu
    Xiaoqing Zhao
    Yilin Pang
    Xinjie Liu
    Jiawei Zhang
    Lei Ma
    Wenxiang Li
    Xue Yao
    Shiqing Feng
    Neural Regeneration Research, 2024, 19 (02) : 434 - 439
  • [9] Argatroban promotes recovery of spinal cord injury by inhibiting the PAR1/JAK2/STAT3 signaling pathway
    Zhao, Chenxi
    Zhou, Tiangang
    Li, Ming
    Liu, Jie
    Zhao, Xiaoqing
    Pang, Yilin
    Liu, Xinjie
    Zhang, Jiawei
    Ma, Lei
    Li, Wenxiang
    Yao, Xue
    Feng, Shiqing
    NEURAL REGENERATION RESEARCH, 2024, 19 (02) : 434 - 439
  • [10] Role of STAT3 in activation of spinal astrocytes and neuropathic pain after peripheral nerve injury
    Tsujikawa, Tomoko
    Tsuda, Makoto
    Yano, Takayuki
    Inoue, Kazuhide
    JOURNAL OF PHARMACOLOGICAL SCIENCES, 2009, 109 : 51P - 51P