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RIPK3 regulates microglial polarization through the TLR4/MyD88 pathway in neuropathic pain

Sihan E1, Qingbiao Song1, Zhaokun Zhang2

  • 1School of Anesthesiology, Shandong Second Medical University, Weifang, China.

Molecular Pain
|August 30, 2025
PubMed

Insights

Receptor-interacting protein kinase 3 (RIPK3) drives neuropathic pain by promoting M1 microglial polarization via the TLR4/MyD88 pathway. Inhibiting RIPK3 alleviates pain and shifts polarization to M2, offering a new therapeutic target.

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Peripheral nerve injury triggers microglial activation and polarization in the spinal cord, contributing to neuropathic pain.
  • Necroptosis, a regulated form of cell death involving receptor-interacting protein kinases 3 (RIPK3), is implicated in neurological disorders.

Purpose of the Study:

  • To investigate the role of RIPK3 in regulating microglial polarization through the Toll-like receptor 4 (TLR4)/Myeloid differentiation primary response 88 (MyD88) signaling pathway in the context of neuropathic pain.

Main Methods:

  • A chronic constriction injury (CCI) mouse model was used to induce neuropathic pain.
  • In vitro studies utilized BV-2 microglia models treated with tumor necrosis factor-alpha (TNF-α)/Z-VAD.
  • RIPK3 inhibition was achieved using GSK'872, and TLR4 antagonism was employed.

Main Results:

  • CCI induced M1 microglial polarization and activated the TLR4/MyD88 pathway in the spinal cord.
  • TNF-α/Z-VAD treatment promoted M1 polarization via TLR4/MyD88 in microglia, an effect blocked by TLR4 antagonists.
  • GSK'872 administration inhibited the TLR4/MyD88 pathway, reduced M1 polarization, enhanced M2 polarization, and alleviated CCI-induced hyperalgesia.

Conclusions:

  • Necroptosis, mediated by RIPK3, is a critical cellular mechanism in peripheral nerve injury-induced neuropathic pain.
  • RIPK3 regulates microglial polarization through the TLR4/MyD88 signaling pathway.
  • Targeting RIPK3 offers a potential therapeutic strategy for neuropathic pain treatment and prevention.
Keywords:
Neuropathic painRIPK3TLR4microglianecroptosis

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