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In Vitro Analysis of E3 Ubiquitin Ligase Function
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E3 Ubiquitin Ligase c-cbl Inhibits Microglia Activation After Chronic Constriction Injury

Pengfei Xue1, Xiaojuan Liu2, Yiming Shen3

  • 1Department of Spine Surgery, the Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.

Neurochemical Research
|June 24, 2018
PubMed

Insights

The E3 ubiquitin ligase c-Cbl negatively regulates neuropathic pain by inhibiting microglial activation and pro-inflammatory cytokine release via the ERK pathway after chronic constriction injury.

Area of Science:

  • Neuroscience
  • Immunology
  • Molecular Biology

Background:

  • E3 ubiquitin ligase c-Cbl (cellular Caritas B cell lymphoma) plays a role in immune regulation.
  • The function of c-Cbl in neuropathic pain following chronic constriction injury (CCI) remains uncharacterized.

Purpose of the Study:

  • To investigate the expression and function of c-Cbl in the context of CCI-induced neuropathic pain.
  • To elucidate the molecular mechanisms underlying c-Cbl's role in pain regulation.

Main Methods:

  • Utilized a rat model of CCI to induce neuropathic pain.
  • Assessed microglial activation and pro-inflammatory factor release (TNF-α, IL-1β, IL-6).
  • Investigated the involvement of the extracellular signal-regulated kinase (ERK) pathway.
  • Employed siRNA to modulate c-Cbl expression in primary microglia.

Main Results:

  • CCI reduced c-Cbl expression, leading to microglial activation and increased release of TNF-α, IL-1β, and IL-6.
  • c-Cbl inhibited microglial activation and pro-inflammatory factor release, alleviating mechanical and heat pain.
  • Down-regulation of the ERK pathway by c-Cbl was crucial for its pain-alleviating effects.
  • Exogenous TNF-α decreased c-Cbl protein levels, while TNF-α inhibition did not alter IL-1β and IL-6 secretion in c-cbl siRNA-transfected microglia.

Conclusions:

  • CCI induces neuropathic pain by down-regulating c-Cbl, activating microglia, and promoting inflammatory factor release via the ERK pathway.
  • c-Cbl acts as a negative regulator of microglial activation and inflammation in neuropathic pain.
  • c-Cbl represents a potential therapeutic target for managing CCI-induced neuropathic pain.
Keywords:
Chronic constriction injury (CCI)Extracellular signal-regulated kinase (ERK)Inflammatory factorsMicrogliac-Caritas B cell lymphoma (c-cbl)

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