Neurochemical Research

, Volume 43, Issue 8, pp 1631–1640 | Cite as

E3 Ubiquitin Ligase c-cbl Inhibits Microglia Activation After Chronic Constriction Injury

  • Pengfei Xue
  • Xiaojuan Liu
  • Yiming Shen
  • Yuanyuan Ju
  • Xiongsong Lu
  • Jinlong Zhang
  • Guanhua Xu
  • Yuyu Sun
  • Jiajia Chen
  • Haiyan Gu
  • Zhiming CuiEmail author
  • Guofeng BaoEmail author
Original Paper


E3 ubiquitin ligase c-Caritas B cell lymphoma (c-cbl) is associated with negative regulation of receptor tyrosine kinases, signal transduction of antigens and cytokine receptors, and immune response. However, the expression and function of c-cbl in the regulation of neuropathic pain after chronic constriction injury (CCI) are unknown. In rat CCI model, c-cbl inhibited the activation of spinal cord microglia and the release of pro-inflammatory factors including tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and interleukin 6 (IL-6), which alleviated mechanical and heat pain through down-regulating extracellular signal-regulated kinase (ERK) pathway. Additionally, exogenous TNF-α inhibited c-cbl protein level vice versa. In the primary microglia transfected with c-cbl siRNA, when treated with TNF-α or TNF-α inhibitor, the corresponding secretion of IL-1β and IL-6 did not change. In summary, CCI down-regulated c-cbl expression and induced the activation of microglia, then activated microglia released inflammatory factors via ERK signaling to cause pain. Our data might supply a novel molecular target for the therapy of CCI-induced neuropathic pain.


c-Caritas B cell lymphoma (c-cbl) Microglia Inflammatory factors Extracellular signal-regulated kinase (ERK) Chronic constriction injury (CCI) 



This work was supported by the National Natural Science Foundation of China (Nos. 81501076, 81401365), the Science and Technology of construction and people’s livelihood Foundation of Jiangsu Province (BL2014061), Jiangsu Province Young Medical Key Talents Project of China (QNRC2016407), the Nantong Science and Technology Innovation Project (No. MS12015056); and the 14th Six Talents Peak Project of Jiangsu Province (No. SWYY-058), and National Natural Youth Science Fund (No. 81702216).

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.


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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Spine Surgerythe Second Affiliated Hospital of Nantong UniversityNantongChina
  2. 2.Department of Pathogen Biology, Medical CollegeNantong UniversityNantongChina
  3. 3.Department of CardiologyAffiliated Hospital of Nantong UniversityNantongChina
  4. 4.Medical CollegeNantong UniversityNantongChina

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